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PHYSIOLOGY 26: 54 – 69, 2011; doi:10.1152/physiol.00024.2010
Oxidative Stress and Cell Membranes in
the Pathogenesis of Alzheimer’s Disease
Amyloid ␤ proteins and oxidative stress are believed to have central roles in
the development of Alzheimer’s disease. Lipid membranes are among the
Paul H. Axelsen,1,2 Hiroaki Komatsu,1
and Ian V. J. Murray3
Departments of 1Pharmacology, 2Biochemistry and Biophysics,
and Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania; and 3Department of Neuroscience
and Experimental Therapeutics, Texas A&M Health Science
Center, College Station, Texas
most vulnerable cellular components to oxidative stress, and membranes in
susceptible regions of the brain are compositionally distinct from those in
other tissues. This review considers the evidence that membranes are either a
source of neurotoxic lipid oxidation products or the target of pathogenic
processes involving amyloid ␤ proteins that cause permeability changes or ion
disease pathogenesis is discussed in which lipid membranes assume both
roles and promote the conversion of monomeric amyloid ␤ proteins into
fibrils, the pathognomonic histopathological lesion of the disease.
The literature of Alzheimer’s disease (AD) research
is vast, complex, and often contradictory. Nevertheless, a broad perspective on this literature, and
on what typically does and does not happen in
biological systems, suggests either that lipid membrane damage is directly involved in the pathogenesis of AD or that it is an important consequence of
AD. Therefore, investigations into the relationship
between membrane damage and amyloidogenesis
may yield important insights into AD pathogenesis.
The “amyloid hypothesis” has driven much of
the research on AD pathogenesis since it was proposed in 1991 (123, 124). In its simplest form, this
hypothesis suggests that the accumulation of amyloid beta (A␤) proteins in brain tissue drives the
pathogenesis of AD. A␤ proteins originate from a
large transmembrane protein of unknown function
known as amyloid precursor protein (APP) by the
action of ␤-secretase and ␥-secretase activity
(FIGURE 1). The specific cleavage site of ␥-secretase is somewhat variable, yielding proteins ranging from 39 to 43 residues in length, with 40 and 42
residue forms predominating (A␤40 and A␤42).
The non-amyloidogenic pathway for APP processing involves ␣-secretases, a family of enzymes that
cleave APP near the middle of the A␤ protein
segment.
The amyloid hypothesis was initially based on
genetic studies of familial AD and the occurrence
of AD-like pathology in Down Syndrome. Among
the most cited experimental studies in support of
this hypothesis are those in which A␤ proteins
impair physiological and cognitive function when
injected into rodent brains (72, 136, 184, 282, 320,
336). Nevertheless, the amyloid hypothesis has
been criticized for being incomplete and vague.
54
For example, it is unable to explain nonfamilial or
sporadic cases of AD (the most prevalent form),
how fibril formation leads to neuronal death, the
poor clinicopathological correlation between amyloid plaque burden and cognitive impairment
(279), the hyperphosphorylation and aggregation
of tau proteins as neurofibrillary tangles, and axonopathies that precede amyloid deposition (302).
These criticisms notwithstanding, there are no alternative hypotheses with nearly as much support,
and the amyloid hypothesis is readily adapted to
answer some of these criticisms. For example, the
pathologies that precede amyloid deposition may
be due to prefibrillar intermediate forms of A␤
protein, and plaques may represent an inert form
of the protein (62, 125, 337). Supporting this idea is
the observation that a variant form of A␤ that oligomerizes but does not fibrillize can nonetheless
cause several pathological manifestations of AD
other than fibril formation (318).
It has been suggested that there is a tenuous
balance among the rates of A␤ protein production,
aggregation, and elimination in brain tissue, such
that a small disturbance applied over sufficient
time causes the pathological accumulation of A␤
protein as amyloid fibrils in AD. However, the concentrations of A␤ proteins in the brain appear to be
far lower than their aqueous in vitro solubility (143,
238, 281). Therefore, A␤ proteins should not form
amyloid fibrils in the brain even if concentrations
are modestly elevated. Yet, fibrils do form with
advancing age in virtually everyone, indicating that
factors other than A␤ protein concentration must
have a role in causing them to form. If small
changes in protein concentration cannot account
for fibril formation, then we must consider factors
1548-9213/11 ©2011 Int. Union Physiol. Sci./Am. Physiol. Soc.
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channel formation. Progress toward a comprehensive theory of Alzheimer’s
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such as macromolecular crowding (216, 228),
locally high concentrations of A␤ proteins at synapses (71), chemical modification (30, 161, 231,
287, 360), cross-linking (17, 22, 290, 291), or metal
complex formation (6, 31, 92, 105, 153, 272, 284,
306). Understanding the chemical mechanisms
that reduce the solubility of A␤ proteins in brain
tissue is key to understanding why AD pathology
develops in some individuals and not others.
Oxidative Stress
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Oxidative stress is caused by a dense, complex and
heterogeneous network of oxidizing reactions running
counter to the reducing conditions that otherwise prevail in cells and tissues. It has been suggested that the
accumulation of A␤ proteins in the brain may be a
protective response to oxidative stress (16, 28, 162, 164,
273, 292). The density of plaques containing A␤ protein
correlates inversely with markers of oxidative damage
(75), and the cortical deposition of A␤ proteins
correlates with reduced oxidative damage in
Down syndrome (236). Moreover, A␤ proteins prevent lipoprotein oxidation (163) and metal-induced
neuronal death in culture (363). However, it is inherently difficult to quantify oxidative stress, and attempts
to do this are subject to many methodological pitfalls.
For example, a study concluding that the primary
mechanism of A␤ toxicity does not involve oxidative
pathways measured thiobarbituric acid reactive substances (TBARS) to assess lipid peroxidation (248).
However, assays for TBARS measure only a small subset of the diverse oxidation products generated, as well
as substances not derived from lipids. Other studies
suggesting that A␤ has antioxidant activity were not
controlled for the inherent redox activity of peptide
groups or conducted in the presence of biologically
relevant electron donors and acceptors to drive the
reactions (23, 24).
Overall, it seems more likely that A␤ proteins
promote oxidative stress (42, 50, 91, 201, 202, 254).
The brain in AD appears to sustain more oxidative
damage than normal brain (200, 211, 331), exhibits
an increased susceptibility to oxidative stress (190,
220, 277), and has relatively low levels of naturally
occurring antioxidants such as ␣-tocopherol (144,
358). Regions of the brain rich in A␤ proteins also
have increased levels of protein oxidation (129).
The overexpression of A␤ proteins in transgenic
mice, in C. elegans, and in cell culture, increases
biomarkers of oxidative stress (256, 345). A␤ proteins cause H2O2 and lipid peroxides to accumulate in cells (27). Catalase protects cells from A␤
toxicity, and cell lines selected for resistance to A␤
toxicity also become resistant to the cytotoxic action of H2O2. A␤ proteins promote the oxidation of
compounds such as dopamine, phospholipids, and
cholesterol (40, 134, 135, 235, 241, 257, 356) as long
as an intact methionine side chain is present (5, 21,
45, 47, 49, 232).
A␤ proteins and amyloid plaques bind redoxactive transition metals that are likely to be the
actual site of redox activity (76, 273). Copper levels
are significantly increased in amyloid plaques (183,
191, 304), although comparatively subtle increases
in copper transport across cell membranes may
cause significant changes in A␤ protein turnover
(321). Excess dietary copper increases AD-like pathology in a mouse model (160). Cu2⫹ and Zn2⫹
chelators appear to inhibit A␤ deposition in the
brains of mouse models (64), and metal depletion
promotes the disaggregation of A␤ fibrils (65).
Cu2⫹ potentiates the neurotoxicity of A␤42 ⬎ A␤40
in embryonic rodent neurons, and its effect is mediated by H2O2 (135, 355). Studies of copper in the
pathogenesis of AD have been extensively reviewed
(39, 90, 100, 305). In contrast, Zn2⫹ ions are redoxinert and able to protect/rescue human cells in
tissue culture from A␤ and Cu2⫹ toxicity (75). A
recent study, however, observed that the zinc released at synapses with neurotransmitters caused
the accumulation of toxic A␤ oligomers to these
membranes (86).
It has been suggested that A␤ proteins split into
fragments that are both neurotoxic and able to
generate additional oxygen radicals (48, 128), although these findings have been strongly refuted
(89). Nevertheless, electron paramagnetic resonance spectroscopy has shown that there is a
strong correlation between the intensity of radical
generation by A␤ and neurotoxicity (219). In these
studies, preincubation of A␤ to form fibrils increased its toxicity. In contrast, replacing the redox-active sulfur atom in residue Met35 with
methylene (CH2) resulted in a peptide that formed
fibrillar structures but had no demonstrable toxicity toward cultured hippocampal neurons. In the
same experimental system, vitamin E (presumably
acting as an antioxidant) neutralized the neurotoxicity of A␤ but had no effect on its ability to form
FIGURE 1. Processing of the amyloid precursor protein
A␤ proteins are 39- to 43-residue segments within the 770-residue amyloid precursor
protein (APP), beginning at residue 672. The non-amyloidogenic processing pathway is
catalyzed by ␣-secretase, which cleaves in the midst of the A␤ protein segment. The
amyloidogenic pathway is catalyzed by ␤-secretase, which cleaves an extracellular site of
APP, and ␥-secretase, which cleaves at points within the transmembrane segment.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
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Enter Lipid Membranes
Investigations into the role of lipids in AD are experimentally challenging because they are chemically diverse, with thousands of distinct molecular
species present in every cell. They are also physically diverse, rarely existing as monomeric species
in solution unless protein bound. In vitro, the vast
majority form micelles or vesicles, and the latter
may be unilamellar or multilamellar. Thus lipid
suspensions generally have two or more phases
and complex interphase equilibria. This physical
heterogeneity complicates most types of physicochemical analysis, even when pure synthetic lipid
preparations are used, and it makes some others
outright impossible. It also impedes the measurement of fibril formation. Turbidity measurements,
for example, are confounded by ambiguity over
whether the species causing the turbidity is protein
or lipid. Lipids markedly increase the fluorescence
of the thioflavin T apart from fibril formation,
whereas assays based on Congo Red absorbance
ratios entail practical restrictions on protein and
lipid concentrations that limit the flexibility of this
assay. The presence of membranes can also complicate sample preparation, and they yield artifacts
when the halogenated solvents used to disaggregate A␤ proteins are not completely removed (56,
310).
Due in part to these challenges, the evidence
that cell membranes are involved in the pathogenesis of AD remains largely circumstantial, even
though the amount of evidence pointing to some
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PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
type of link is overwhelming. A␤ proteins are produced by cleavage of APP at two sites, one site
being located approximately at the midpoint of the
transmembrane segment (FIGURE 1). As a consequence, the COOH-terminal residues of A␤ proteins that were part of the APP transmembrane
segment are uniformly hydrophobic. Following
their cleavage from APP, some investigators have
observed that A␤ proteins remain associated with
detergent-resistant lipid membrane domains in
the brain (181), or with membrane-anchored APP
(189). It has also been hypothesized that A␤ proteins bind to the transmembrane helices of membrane proteins and cause their dysfunction (199).
Ultrastructural studies suggest that amyloid fibril
formation tends to occur first in portions of diffuse
amyloid deposits that are closest to membranes
(234, 319, 346). A␤40 with the E22Q mutation (responsible for hereditary cerebral hemorrhage with
amyloidosis-Dutch type) will fibrillize on the surface membrane of human cerebrovascular smooth
muscle cells (330).
Despite a substantial hydrophobic segment, the
general conclusion reached by most investigators
is that A␤ proteins have little affinity for neutral
lipid membranes (205). Techniques such as the
hydration of a mixed protein-lipid film must be
used to induce the penetration of A␤ proteins into
a neutral lipid bilayer (83). One laboratory investigating A␤40 and another investigating A␤42 have
documented that the proteins situate differently in
membranes depending on whether they are embedded in a bilayer membrane or allowed to associate with the surface of a preformed membrane
(33, 106, 176). In general, anionic lipids tend to
induce A␤ proteins to adopt extended ␤ structure
(35, 63, 66, 76, 130, 167–169, 204, 213, 214, 313, 314,
344, 352). Possible reasons for the inducement of ␤
structure and fibril formation by protein-lipid interaction have been reviewed, including the ability
of such interactions to serve as templates for structural change, to increase the local concentration of
protein, and to orient protein monomers relative to
each other (2, 113). A␤ proteins adopt ␣-helical
structure in association with lipid membranes at
low lipid-to-protein ratios (315), at high cholesterol
concentrations (145), or in conjunction with metal
ions (21, 76, 77). Some investigators have found that
detergent micelles promote ␣-helical structure (283),
whereas others find that it promotes the formation of
oligomers with ␤ structure (261). Spontaneous insertion into various membranes has been observed for
A␤ segments (82) and for A␤ proteins at relatively low
membrane surface pressures (94).
The relative abundance of various lipid classes in
membranes is altered in AD (121, 227, 247, 252,
350), and altering membrane composition protects
PC12 cells from toxic effects of A␤ proteins (338).
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fibrils (332). Another study concluding that free
radicals do not mediate A␤-induced neurotoxicity
used ginkgolides (a purported anti-oxidant component of Ginkgo biloba leaves) and vitamin E to
inhibit oxidation (351). Although neither agent
protected cells from apoptosis and death, it is unlikely that they completely halted radical-mediated
oxidative damage.
Proteomics studies of oxidative stress have focused on proteins damaged by oxidation, nitration,
and other reactive substances (41, 44, 50, 51, 57, 58,
60, 80, 107, 243, 285, 293, 317). In most cases,
reactions with protein carbonyl groups are taken
for evidence of damage by oxidation, and the nature of the protein modification is not explicitly
defined. Two studies have examined the ability of
A␤ proteins to induce oxidative modifications in
other proteins (34), and A␤ proteins may also undergo oxidative damage, particularly His, Tyr, and
Met side chains (15, 32, 43, 132, 139). However, it is
difficult to imagine how oxidative damage to proteins, especially A␤ proteins, would lower the
aqueous solubility of A␤ proteins and promote fibril formation.
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with lovastatin/mevalonate alone, however, was insufficient to induce a significant effect; treatment
with ␤-cyclodextrin to achieve a 70% reduction of
cellular cholesterol content was also required. It has
been suggested that the dependence of A␤ protein
production on cholesterol is due to the selective activity of ␤-secretase activity in cholesterol-dependent
raft-like subdomains of the plasma membrane,
whereas ␣-secretase activity appears to predominate
in non-raft domains (95). Some ␤-secretase stimulation has also been attributed to neutral glycosphingolipids and anionic phospholipids (152). The
efficacy of a ␤-secretase inhibitor has been increased
by linking it to cholesterol and thereby targeting it to
membranes (260).
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Altered physical properties, presumably arising
from compositional differences, have been observed in hippocampal membranes of AD brains
(364). Plasmalogen deficiency is frequently associated with AD (102, 110 –112, 119, 120, 229). In addition to having an effect on membrane physical
properties, plasmalogens are particularly susceptible to oxidative damage (156 –158). This susceptibility may confer on plasmalogens the ability to
protect other lipid species by diverting and trapping oxidizing agents (36, 117, 118, 170, 195, 196,
222, 230, 242, 264, 362). Cerebral white matter is
enriched in plasmalogens for unknown reasons
(101).
Human epidemiological studies support a link
between AD and the consumption of ␻-3 polyunsaturated fatty acyl (PUFA) chains (103, 141, 223,
224, 237, 250, 275, 323), and this association is
supported by animal model and cell culture studies (53–55, 126, 146, 185, 193, 350). The most prevalent ␻-3 PUFA in the brain is docosahexaenoic
acid (DHA), and dietary DHA supplementation alleviates both AD-like histopathology and cognitive
impairment in animal models (53, 55, 126, 185).
The metabolism of DHA in normal brain is remarkable in several respects (159), and it is difficult to
induce a measurable deficiency of DHA-containing
lipids in the brain tissue of animal models through
dietary restriction (84). Animal studies have shown
that the brain responds to a dietary deficiency of
DHA by elongating arachidonic acid (ARA) chains.
Because there are no enzymes capable of desaturating the distal end of these PUFA chains, the
result is a marked increase in docosapentaenoic
acid (DPA) chains (138).
A␤ proteins appear to have special relationships
or interactions with specific lipid species. For example, the ganglioside GM1 is bound together with
A␤ proteins in diffuse amyloid plaques (348). GM1containing membranes promote the formation of
␣ structure (212, 215), ␤ structure (206), or fibrils in
vitro (67– 69, 115, 127, 148 –151, 165, 207, 218, 239,
240, 334, 335). In several of these reports, GM1 is
presented in raft-like membrane subdomains in
which cholesterol is a significant component, and
rafts have also been discussed as an influence on
the processing of APP into A␤ proteins (74). Apart
from rafts, cholesterol has been epidemiologically
(289, 311) and experimentally (263, 300) linked to
the incidence of AD, and it may influence the production (108, 361), location (77, 87, 145), behavior
(79, 214, 352), or toxicity (38, 78, 137, 308, 338) of
A␤ proteins. In models of Niemann-Pick Type C
disease, A␤ proteins accumulate along with cholesterol (347).
Cholesterol depletion reduced the ␤-cleavage of
APP and the production of A␤ proteins in a study of
neurons in the rat hippocampus (288). Treatment
The Membrane as Villain
The lipids in cell membranes are often regarded as
being chemically unreactive and merely a physical
barrier or a support matrix for proteins. That view
is misleading on many levels, of course, but particularly so when the membrane lipids contain
PUFA chains and are subjected to oxidative stress.
Reviews of the role of membranes in AD pathogenesis frequently overlook the effects of oxidative
stress and chemical modification of PUFA chains
on membrane properties. A␤ proteins have a
prooxidant activity toward polyunsaturated lipids
that can be neutralized by lipophilic antioxidants,
chelation of metal ions, anaerobic conditions, mutation of His13 or His14 to Ala, or modification of
the Met35 side chain (232). Lipid oxidation products and the susceptibility of lipids to oxidative
damage are both increased in AD (78, 104, 210,
309). Several reports have outlined the potential for
a complex interplay between cholesterol oxidation
products and A␤ proteins (38, 116, 235, 241, 301,
329, 356, 360).
The myriad mechanisms of oxidative stress yield
diverse chemically reactive products from PUFA
chains including hydroxy- and hydroperoxy-lipids
that undergo spontaneous decomposition, lipid
free radicals that may participate in free-radical
chain reactions, as well as fragments such as malondialdehyde, acrolein, and hydroxynonenal with
the potential to form adducts with proteins and
nucleic acids (61, 270, 274, 293, 295, 296). These
materials are direct toxic threats to the tissues in
which they are generated. Brain is the most lipidrich organ in the body, and it contains more lipids
bearing PUFA chains than any other organ. Therefore, brain tissue is at particularly high risk for
chemical injury due to highly reactive lipid oxidation products.
Evidence that lipid peroxidation may be involved
in the pathogenesis of AD has been extensively
reviewed (13, 42, 46, 201). Lipid hydroperoxides
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PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
ble for generating HNE from ␻-6 PUFAs. Consequently, HNE-His epitopes would develop around
preexisting amyloid plaques, not within them. A
second possibility is that A␤-specific antibody
epitopes are masked by HNE modification, as observed in vitro for 4G8 and 6E10 epitopes (231). A
third possibility is that A␤ fibrils induced to form
by HNE modification have relatively sparse HNEHis epitopes (as suggested by FIGURE 2), yielding
sparse fluorescence among fibrils. The fluorescence of HNE-11S seen in FIGURE 3 may be to
HNE produced in the plaque but bound to HNEHis adducts in proteins other than A␤ proteins.
Some investigators have focused on the role of
acrolein in the pathogenesis of AD. Acrolein is a well
known environmental toxin and a recently recognized product of lipid peroxidation (324, 326, 327). It
reacts spontaneously with Lys residue side chains,
forming a cyclic Nε-(3-formyl-3,4-dehydropiperidino) derivative that has been considered a
biomarker for measuring oxidative stress in AD
(52). Acrolein is elevated in AD brain, it appears
to be more neurotoxic than HNE, it causes elevated intracellular calcium levels (192, 342), and
it appears to inactivate flippase, inducing a
breakdown of lipid membrane asymmetry and
apoptosis (1, 59).
The Membrane as Victim
Although the foregoing discussion suggests that AD
may be caused by membrane-derived neurotoxic
agents, a contrasting view is that AD is due to
FIGURE 2. Electron micrograph of fibrils induced
by HNE modification
A␤42 was induced to fibrillize with HNE, then treated
with mouse anti-His-HNE, and gold-tagged anti-mouse
antibody. The focus in this image is on the gold particles, but various fibril morphologies are evident, and the
gold particles making anti-HNE-His antibodies are preferentially associated with long, relatively straight fibils.
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undergo spontaneous (nonenzymatic) decomposition, and ␻-6 PUFA chains yield reactive ␣,␤-unsaturated aldehydes such as 4-oxo-2(E)-nonenal
(180) and 4-hydroxy-2(E)-nonenal (HNE) (97, 98),
as well as eicosanoids such as isoprostanes (225,
226). The prooxidant activity of A␤ proteins mentioned above can catalyze the formation of HNE
from ␻-6 PUFAs in the presence of copper ions
(232). Isoprostanes are relatively unreactive compounds that have been used as biomarkers of oxidative stress (179, 221, 244, 268). Some reports
suggest that isoprostanes are specifically elevated
in AD (253, 255, 256), although these findings have
not been confirmed by all investigators (221, 357).
Analogous products derived from ␻-3 PUFA chains
have been dubbed “neuroprostanes” and also have
been put forward as indexes of oxidative stress in
the brain (14, 266, 267, 298).
Compared with isoprostanes, HNE is chemically
reactive, with a well known propensity to form
adducts with the side chains of various amino acid
residues (37, 98, 328). For this reason, HNE-protein
adducts have also been used as biomarkers of oxidative stress (325). HNE concentrations in human
ventricular fluid are ⬃15 ␮M and are elevated in
AD (190, 203, 210). HNE modification is also known
to inhibit proteasome function (286) and glutamate transport in synaptosomes (177). Together
with the observation that immunoreactivity of antibodies to HNE-modified His residues localizes to
amyloid plaques (7, 294), these observations suggest that A␤ proteins not only promote lipid oxidation but that there may also be a mechanistic
link between the lipid oxidation products formed
during oxidative stress and A␤ misfolding (161).
A␤ proteins increase HNE production from PUFA
chains in vitro that, in turn, causes covalent modification of the three His residues in A␤ proteins and
fibril formation (231). These modifications promote
the aggregation of A␤ proteins into fibrils (FIGURE 2)
(165, 231, 232). Moreover, they increase the ability of
A␤42 to seed fibril formation by unmodified A␤40
(166). The effects of HNE on A␤ fibril formation depend on the size or hydrophobicity of the modification because the corresponding analog from ␻-3
PUFA chains, 4-hydroxy-2(E)-hexenal, does not have
this effect (187). The addition of an octanoyl group to
specific Lys residues of A␤ proteins also appears to
have a pro-amyloidogenic effect (258).
In vivo, HNE-His epitopes are concentrated in
the vicinity of amyloid plaques, but they do not
precisely co-localize with the plaques (FIGURE 3).
One possible explanation for this distribution is
that the presence of HNE-His adducts and Cu-His
complexes in the same protein molecule are mutually exclusive. Presumably, the formation of CuHis complexes precedes the generation of HNE
and HNE-His adducts, if indeed they are responsi-
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toxic properties of A␤ proteins on a membrane depends on the extent to which it has aggregated into
oligomers and that this extent is concentration dependent (276). Model structures of the purported
channels have been patterned after ␤-barrel poreforming toxins (8, 93). This comparison is suggested
not only by the EM/AFM images but by the reactivity
of A␤ and ␣-hemolysin with so-called “conformation-specific” antibodies (354). Recent studies confirming the formation of zinc-sensitive ion channels
have also exposed the potential for artifact due to
residual amounts of halogenated solvent in the A␤
protein samples (56).
It may be significant that truncated A␤ peptides
that are unable to form fibrils can nevertheless
induce ion permeability (142) and that membranes
formed from highly compressible lipids are most
sensitive to A␤-induced changes in permeability
(297). It has been suggested that channel openings
are merely protein-induced defects in the bilayer
structure or organization that heal after a time,
giving the appearance of a transient channel opening (114). This mechanism would be consistent
with oligomer-induced membrane thinning (297)
and would help resolve the paradoxical appearance of many simultaneous pore structures in
membranes that exhibit only single channel conductances (96).
In living cells, as opposed to synthetic systems,
one must consider the possibility that A␤ may profoundly affect the behavior of naturally occurring
channels and transporters. For example, A␤42 increases HNE-modification of a glutamate transporter in synaptosomes (177). A␤ oligomers have
been implicated in causing a pathological calcium
influx through hippocampal NMDA receptors, followed by the activation of calpain and the degradation of dynamic 1-a GTPase involved in synaptic
vesicle recycling (155). A␤ proteins have also been
shown to depress the surface concentration of
AMPA receptors involved in calcium regulation at
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physical attacks on the barrier function of membranes (265). For example, A␤ proteins or their
fragments have been observed to penetrate the
membrane surface (82, 94), disrupt raft-like domains (67), cross the membrane (341), induce isotropic phases (176), increase the permeability of
membranes to various materials (154, 344), cause
physical thinning (81), decrease the mobility of
hydrophobic membrane probes (169), activate
phospholipase A2 (182), and promote membrane
fusion (81, 249). Membrane binding by A␤ proteins
appears to mediate some forms of neurotoxicity
(21, 70, 316). Plasma membranes isolated from human brain accelerate A␤ fibrillogenesis (339),
whereas fibrillizing A␤ proteins disrupt the structure of membranes formed from both synthetic
lipids (168, 169) and whole-brain lipid extracts
(353). The action of A␤ proteins on membranes has
been compared with the action of antimicrobial
peptides, and homogenates of brain with AD have
elevated antimicrobial activity (299). Among the
effects of A␤ proteins on membranes, however, the
formation of ion channels has received the most
attention (10 –12, 93, 147, 186, 251).
A␤ proteins share an ability to induce channel-like
activity in membranes with a wide variety of other
amyloid-forming proteins (259). In the case of A␤, the
channels exhibit only modest cation selectivity but
very long lifetimes. A␤ cation channels can be
blocked by Zn2⫹, suggesting the possibility that they
may be therapeutic targets (9), and small molecule
inhibitors of the A␤ calcium channel have been described (88). Ring-like structures possibly representing these pores or channels have been observed in
membranes by AFM (173, 186, 259) and EM (174,
175). Although such features are not always observed
with A␤ proteins (114, 341), there are many reports
suggesting that they are formed by other amyloidogenic proteins such as the insulin-associated polypeptide, ␣-synuclein, and serum amyloid A protein
(259). It has been suggested that the channel-forming
FIGURE 3. Immunofluorescent staining of the posterior parietal association area in a transgenic mouse model of Alzheimer’s
disease that expressed amyloid precursor protein with the “Swedish” K670N/M671L mutation, and presenilin 1 with the
M146L mutation
A: 2H4 antibodies (Covance) specific for the amino terminus A␤ proteins (green). B: HNE 11S specific for HNE-His adducts (red). C: A and B
superimposed. Possible reasons for the close association of HNE-His epitopes and A␤ proteins, but not precise colocalization, are discussed
in the text.
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the synapse (133, 188). The dysregulation of calcium has long been associated with AD pathogenesis (172) and is thought to be involved with the
accumulation of amyloid deposits (85, 208, 209)
and the hyperphosphorylation of tau (25). Calcium
also promotes the conversion of oligomeric A␤ to
fibrils (140). An extensive literature exists on the
role of mitochondria in AD pathogenesis, and the
accumulation of calcium by mitochondria followed by damage to the mitochondrial membrane
structure is a prominent theme in this literature
(131, 246, 262).
The lipids in nascent lipoprotein particles are arranged in a membrane-like bilayer, surrounded by
apolipoprotein molecules in a configuration often
called the “belt” model (FIGURE 4) (280). Apolipoprotein E (ApoE) is a focus of considerable interest
because its isoforms are strongly associated with
the risk of developing AD. In plasma, ApoE is found
with other proteins in lipoprotein particles as diverse as chylomicrons and high-density lipoproteins. In the brain and cerebrospinal fluid, ApoE is
the most abundant apolipoprotein and is found in
particles that resemble high-density lipoproteins
in both density and size (269). Among the three
common isoforms, ApoE3 is the most common
(77% of the alleles) and is therefore considered to
be the wild type. ApoE2 has an R158C substitution,
whereas ApoE4 has a C112R substitution, and both
are associated with forms of hyperlipidemia (197).
One copy of the ApoE4 gene confers a threefold
increased risk of Alzheimer’s disease, whereas two
FIGURE 4. Nascent lipoprotein E particles consist of
␣-helical “belts” around the perimeter of a lipid bilayer
disk
For this arrangement and the number of protein and lipid molecules in a particle, there is excess protein, which may situate
across the face of the disk. When the protein is apoE3, there is
one thiol group for every 45 lipids, concentrating a large antioxidant capacity in close proximity to the lipids.
60
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
Toward a Comprehensive Theory
of AD Pathogenesis
The cause of AD is known in cases of familial
disease, but that knowledge has not clarified how
sporadic disease develops, nor has it so far yielded
an effective therapy for either form of the disease.
Clearly, we need a more detailed theory of AD
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The Lipids Associated With
Apolipoprotein E
copies confer an eightfold increased risk. One copy
of the ApoE2 gene, however, reduces the risk by
60% (73).
In addition to the epidemiological evidence,
there is an abundance of experimental evidence
linking ApoE to the pathogenesis of Alzheimer’s
disease. For example, the ApoE4 allele is associated
with increased A␤ deposits in the brain, and
a distinct neuropathological phenotype (278),
whereas a lack of ApoE reduces A␤ deposition in
mice (19). Amyloid plaques bind anti-ApoE antibodies, suggesting that ApoE is present in these
plaques (3). Indeed, ApoE copurifies with A␤ from
amyloid plaques (26) and may exist as a bound
complex with A␤ proteins (245, 349). Some have
suggested that ApoE4 accelerates fibril formation
by A␤40 (18, 194, 271, 343), but its behavior in this
regard may depend on whether it is monomeric or
dimeric. Others have suggested that dimeric forms
inhibit fibril formation and that ApoE3 is much
more effective at doing this because a large fraction
circulates as a disulfide-linked dimer, whereas
ApoE4 cannot form disulfide bonded dimers due to
its C112R substitution (99, 340). Despite all of these
observations, the reason that different isoforms of
ApoE have different levels of risk for AD is not known.
There are no isoform-dependent differences in the
apparent structure of lipoprotein particles (280). A
case for isoform-specific direct interactions between
ApoE and A␤ proteins has been made (233), but clear
conclusions are elusive due to problems with protein
purity, aggregation and denaturation of the ApoE
protein, and indirect assay methods (4, 171, 198, 245,
303, 307).
Others have suggested that risk of AD with ApoE
isoforms may be related to differences in antioxidant activity (178, 217, 312). ApoE4 has no Cys
residues and, hence, no free thiol groups; ApoE3
has one Cys, whereas ApoE2 has two. Free thiol
groups have significant antioxidant activity via
mechanisms that differ from those of glutathione
(109, 333, 359). In apoA-I, variants with a free Cys
residue side chain exhibit significantly greater antioxidant activity than variants without a free Cys
residue (29). Therefore, it is intriguing to speculate
that ApoE4 confers increased risk of AD, whereas
ApoE2 confers decreased risk, because Cys residue
side chains protect lipids in lipoprotein E particles
against oxidative stress.
REVIEWS
No conflicts of interest, financial or otherwise, are declared by the author(s).
FIGURE 5. Membrane-mediated amplification of fibrillogenesis, illustrating
possible relationships between meachanisms involved in A␤ protein
aggregation and neurotoxic mechanisms involved in the pathogenesis of
Alzheimer’s disease
Lipid oxidation products modify the three His residues of A␤42, increasing its membrane
affinity and accelerating the conversion of A␤40 into oligomers and fibrils. Oligomeric A␤
proteins bind copper ions while they undergo redox cycling. Highly reactive oxygen species may be generated by electrons from copper or as by-products of inflammation, including inflammation induced by trauma. ApoE4 alleles lack thiol-mediated antioxidant
activity and may allow excess oxidative damage to the lipids in lipoprotein particles. Aging
by itself is associated with reduced tissue antioxidant levels and accumulated oxidative
lipid damage. During any or all of these processes, direct neurotoxins may be produced,
and A␤ proteins may form pores, channels, or other disruptive neurotoxic structures in
neuronal membranes.
The authors are supported by grants from the National
Institute on Aging, the Alzheimer’s Association, and the
American Health Assistance Foundation.
References
1.
Abdul HM, Butterfield DA. Protection against amyloid betapeptide (1-42)-induced loss of phospholipid asymmetry in
synaptosomal membranes by tricyclodecan-9-xanthogenate
(D609) and ferulic acid ethyl ester: implications for Alzheimer’s disease. BBA Mol Basis Dis 1741: 140 –148, 2005.
2.
Aisenbrey C, Borowik T, Bystrom R, Bokvist M, Lindstrom F,
Misiak H, Sani MA, Grobner G. How is protein aggregation in
amyloidogenic diseases modulated by biological membranes? Eur Biophys J Biophys Lett 37: 247–255, 2008.
3.
Aizawa Y, Fukatsu R, Takamaru Y, Tsuzuki K, Chiba H, Kobayashi K, Fujii N, Takahata N. Amino-terminus truncated
apolipoprotein E is the major species in amyloid deposits in
Alzheimer’s disease affected brains: a possible role for apolipoprotein E in Alzheimer’s disease. Brain Res 768: 208 –214,
1997.
4.
Aleshkov S, Abraham CR, Zannis VI. Interaction of nascent
ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1– 40). Relevance to
Alzheimer’s disease. Biochemistry 36: 10571–10580, 1997.
5.
Ali FE, Separovic F, Barrow CJ, Cherny RA, Fraser F, Bush AI,
Masters CL, Barnham KJ. Methionine regulates copper/hydrogen peroxide oxidation products of A beta. J Pept Sci 11:
353–360, 2005.
6.
Ali FE, Separovic F, Barrow CJ, Yao SG, Barnham KJ. Copper
and zinc mediated oligomerisation of A beta peptides. Int J
Pept Res Ther 12: 153–164, 2006.
7.
Ando Y, Brannstrom T, Uchida K, Nyhlin N, Nasman B, Suhr
O, Yamashita T, Olsson T, El Salhy M, Uchino M, Ando M.
Histochemical detection of 4-hydroxynonenal protein in Alzheimer amyloid. J Neurol Sci 156: 172–176, 1998.
8.
Arispe N. Architecture of the Alzheimer’s A beta P ion channel pore. J Membrane Biol 197: 33– 48, 2004.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
61
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
pathogenesis, and it seems likely that lipid membranes will have a prominent role in any such
theory. As summarized above, the interactions between lipid membranes and A␤ proteins are bidirectional: lipids damage A␤ proteins, and A␤
proteins damage lipid membranes. These processes can operate in tandem to accelerate fibril
formation in human brain lipid extracts (231). Even
if fibril formation is only an inert by-product of the
disease-causing process, it is nonetheless a pathognomonic finding of AD. Therefore, it is vital to
understand how fibrils form.
As illustrated in FIGURE 5, the interaction of lipid
membranes may constitute an amplification system for fibril formation. A␤ proteins in vitro only
form fibrils at micromolar concentrations and after
days of incubation, whereas membranes containing PUFA-chains lower the protein concentration
requirement by three orders of magnitude and
shorten the time required to minutes (165, 166).
The same system may also amplify multiple mechanisms of neurotoxicity that operate independently of fibril formation and link many of the
seemingly unrelated observations reviewed above.
For example, inflammation due to trauma or other
factors will promote oxidative stress and the production of reactive oxygen species that exert direct
neurotoxicity or lipid damage and A␤ protein aggregation. Lipid oxidation products may exert
direct toxicity. ApoE4 proteins are deficient in
thiol-mediated antioxidant activity; this deficiency
would allow excess oxidative damage to the lipids
in lipoprotein particles that likewise promote A␤
protein aggregation. Aging is associated with reduced tissue antioxidant levels, accumulated oxidative lipid damage, and low levels of adventitial
A␤ protein aggregation, with each process promoting further A␤ protein aggregation. Various aggregated forms of A␤ protein may form pores,
channels, or other neurotoxic structures in neuronal membranes.
It is not yet clear whether all cases of AD arise
through the operation of one primary pathogenic
mechanism that diverges only at a late stage into
various subtypes or whether disparate mechanisms operate from the beginning. For example,
neurofibrillary tangles of tau protein (20, 322) occur in only 70 – 80% of cases of AD (122), suggesting
that tangles reflect a response to some but not all
pathogenic paths. In any case, one or more additional factors must be incorporated into the amyloid hypothesis to explain the pathogenesis of AD,
and confronting the experimental challenges presented by lipids and membranes may be necessary
to identify such factors. 䡲
REVIEWS
9.
Arispe N, Diaz JC, Simakova OA. ␤ Ion channels.
Prospects for treating Alzheimer’s disease with
A␤ channel blockers. BBA Biomembranes 1768:
1952–1965, 2007.
10. Arispe N, Pollard HB, Rojas E. Giant multilevel
cation channels formed by Alzheimer-disease
amyloid beta-protein [A-Beta-P-(1-40)] in bilayermembranes. Proc Natl Acad Sci USA 90: 10573–
10577, 1993.
11. Arispe N, Pollard HB, Rojas E. Zn2⫹ interaction
with Alzheimer amyloid beta protein calcium
channels. Proc Natl Acad Sci USA 93: 1710 –1715,
1996.
12. Arispe N, Rojas E, Pollard HB. Alzheimer-disease
amyloid beta-protein forms calcium channels in
bilayer-membranes: blockade by tromethamine
and aluminum. Proc Natl Acad Sci USA 90: 567–
571, 1993.
26. Baumann MH, Kallijarvi J, Lankinen H, Soto C,
Haltia M. Apolipoprotein E includes a binding
site which is recognized by several amyloidogenic polypeptides. Biochem J 349: 77– 84, 2000.
27. Behl C, Davis JB, Lesley R, Schubert D. Hydrogen
peroxide mediates amyloid beta protein toxicity.
Cell 77: 817– 827, 1994.
28. Berthon G. Does human beta A4 exert a protective function against oxidative stress in Alzheimer’s disease? Med Hypotheses 54: 672– 677,
2000.
29. Bielicki JK, Oda MN. Apolipoprotein A-I-Milano
and apolipoprotein A-I-Paris exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-I. Biochemistry 41: 2089 –2096,
2002.
14. Arneson KO, Roberts LJ. Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and neurofurans. Lipidomics
Bioactive Lipids 433: 127–143, 2007.
30. Bieschke J, Zhang Q, Powers ET, Lerner RA, Kelly
JW. Oxidative metabolites accelerate Alzheimer’s amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation.
Biochemistry 44: 4977– 4983, 2005.
15. Atwood CS, Huang XD, Khatri A, Scarpa RC, Kim
YS, Moir RD, Tanzi RE, Roher AE, Bush AI. Copper catalyzed oxidation of alzheimer A beta. Cell
Mol Biol 46: 777–783, 2000.
31. Bishop GM, Robinson SR. The amyloid paradox:
amyloid-beta-metal complexes can be neurotoxic and neuroprotective. Brain Pathol 14: 448 –
452, 2004.
16. Atwood CS, Obrenovich ME, Liu TB, Chan H,
Perry G, Smith MA, Martins RN. Amyloid-beta: a
chameleon walking in two worlds: a review of the
trophic and toxic properties of amyloid-beta.
Brain Res Rev 43: 1–16, 2003.
32. Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE, Teplow DB. A molecular
switch in amyloid assembly: Met(35) and amyloid
beta-protein oligomerization. J Am Chem Soc
125: 15359 –15365, 2003.
17. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD,
Ling KQ, Huang XD, Moir RD, Wang DD, Sayre
LM, Smith MA, Chen SG, Bush AI. Copper mediates dityrosine cross-linking of Alzheimer’s amyloid-beta. Biochemistry 43: 560 –568, 2004.
33. Bokvist M, Lindstrom F, Watts A, Grobner G.
Two types of Alzheimer’s beta-amyloid (1-40)
peptide membrane interactions: aggregation
preventing transmembrane anchoring versus accelerated surface fibril formation. J Mol Biol 335:
1039 –1049, 2004.
18. Bales KR, Verina T, Cummins DJ, Du YS, Dodel
TC, Saura J, Fishman CE, DeLong CA, Piccardo P,
Petegnief V, Ghetti B, Paul SM. Apolipoprotein E
is essential for amyloid deposition in the
APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 96:
15233–15238, 1999.
19. Bales KR, Verina T, Dodel RC, Du YS, Altstiel L,
Bender M, Hyslop P, Johnstone EM, Little SP,
Cummins DJ, Piccardo P, Ghetti B, Paul SM. Lack
of apolipoprotein E dramatically reduces amyloid
beta- peptide deposition. Nat Gen 17: 263–264,
1997.
20. Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease
and related disorders. Nat Rev Neurosci 8: 663–
672, 2007.
21. Barnham KJ, Ciccotosto GD, Tickler AK, Ali FE,
Smith DG, Williamson NA, Lam YH, Carrington D,
Tew D, Kocak G, Volitakis I, Separovic F, Barrow
CJ, Wade JD, Masters CL, Cherny RA, Curtain
CC, Bush AI, Cappai R. Neurotoxic, redox-competent Alzheimer’s beta-amyloid is released from
lipid membrane by methionine oxidation. J Biol
Chem 278: 42959 – 42965, 2003.
22. Barnham KJ, Haeffner F, Ciccotosto GD, Curtain
CC, Tew D, Beyreuther K, Carrington D, Masters
CL, Cherny RA, Cappai R, Bush AI. Tyrosine
gated electron transfer is key to the toxic mechanism of Alzheimer’s disease ␤-amyloid. FASEB J
18: 1427–1429, 2004.
23. Baruch-Suchodolsky R, Fischer B. Soluble amyloid beta(1-28)-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free
systems. Biochemistry 47: 7796 –7806, 2008.
24. Baruch-Suchodolsky R, Fischer B. A␤40, either
soluble or aggregated, is a remarkably potent
antioxidant in cell-free oxidative systems. Biochemistry 48: 4354 – 4370, 2009.
62
34. Boyd-Kimball D, Castegna A, Sultana R, Poon HF,
Petroze R, Lynn BC, Klein JB, Butterfield DA.
Proteomic identification of proteins oxidized by
A beta(1-42) in synaptosomes: implications for
Alzheimer’s disease. Brain Res 1044: 206 –215,
2005.
35. Brezesinski G, Maltseva E, Mohwald H. Adsorption of amyloid beta (1-40) peptide at liquid interfaces. Z Phys Chem 221: 95–111, 2007.
36. Brosche T, Platt D. Mini-review: The biological
significance of plasmalogens in defense against
oxidative damage. Exp Gerontol 33: 363–369,
1998.
37. Bruenner BA, Jones AD, German JB. Direct characterization of protein adducts of the lipid-peroxidation product 4-hydroxy-2-nonenal using
electrospray mass-spectrometry. Chem Res Tox
8: 552–559, 1995.
38. Bryleva EY, Rogers MA, Chang CCY, Buen F,
Harris BT, Rousselet E, Seidah NG, Oddo S,
LaFerla FM, Spencer TA, Hickey WF, Chang TY.
ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates
amyloid pathology in mice with AD. Proc Natl
Acad Sci USA 107: 3081–3086, 2010.
39. Bush AI. The metallobiology of Alzheimer’s disease. Trends Neurosci 26: 207–214, 2003.
40. Butterfield DA. Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s
disease brain. A review. Free Radic Res 36: 1307–
1313, 2002.
41. Butterfield DA. Proteomics: a new approach to
investigate oxidative stress in Alzheimer’s disease brain. Brain Res 1000: 1–7, 2004.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
42. Butterfield DA, Boyd-Kimball D. Amyloid betapeptide(1-42) contributes to the oxidative stress
and neurodegeneration found in Alzheimer disease brain. Brain Pathol 14: 426 – 432, 2004.
43. Butterfield DA, Boyd-Kimball D. The critical role
of methionine 35 in Alzheimer’s amyloid-betapeptide (1-42)-induced oxidative stress and neurotoxicity. Biochim Biophys Acta 1703: 149 –156,
2005.
44. Butterfield DA, Boyd-Kimball D, Castegna A. Proteomics in Alzheimer’s disease: insights into potential mechanisms of neurodegeneration. J
Neurochem 86: 1313–1327, 2003.
45. Butterfield DA, Bush AI. Alzheimer’s amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity
properties of this peptide. Neurobiol Aging 25:
563–568, 2004.
46. Butterfield DA, Castegna A, Lauderback CM,
Drake J. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal
death. Neurobiol Aging 23: 655– 664, 2002.
47. Butterfield DA, Galvan V, Lange MB, Tang HD,
Sowell RA, Spilman P, Fombonne J, Gorostiza O,
Zhang JL, Sultana R, Bredesen DE. In vivo oxidative stress in brain of Alzheimer disease transgenic mice: requirement for methionine 35 in
amyloid beta-peptide of APP. Free Radic Biol
Med 48: 136 –144, 2010.
48. Butterfield DA, Hensley K, Harris M, Mattson MP,
Carney JM. Beta-amyloid peptide free-radical
fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications
to Alzheimers-disease. Biochem Biophys Res
Commun 200: 710 –715, 1994.
49. Butterfield DA, Kanski J. Methionine residue 35 is
critical for the oxidative stress and neurotoxic
properties of Alzheimer’s amyloid beta-peptide
1-42. Peptides 23: 1299 –1309, 2002.
50. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer’s disease
brain: potential causes and consequences involving amyloid beta-peptide-associated free radical
oxidative stress. Free Radic Biol Med 32: 1050 –
1060, 2002.
51. Butterfield DA, Reed T, Newman SF, Sultana R.
Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the
pathogenesis of Alzheimer’s disease and mild
cognitive impairment. Free Radic Biol Med 43:
658 – 677, 2007.
52. Calingasan NY, Uchida K, Gibson GE. Proteinbound acrolein: a novel marker of oxidative
stress in Alzheimer’s disease. J Neurochem 72:
751–756, 1999.
53. Calon F, Cole G. Neuroprotective action of
omega-3 polyunsaturated fatty acids against
neurodegenerative diseases: evidence from animal studies. Prost Leuk Essen Fatty Acids 77:
287–293, 2007.
54. Calon F, Lim GP, Morihara T, Yang FS, Ubeda O,
Salem N, Frautschy SA, Cole GM. Dietary n-3
polyunsaturated fatty acid depletion activates
caspases and decreases NMDA receptors in the
brain of a transgenic mouse model of Alzheimer’s
disease. Eur J Neurosci 22: 617– 626, 2005.
55. Calon F, Lim GP, Yang FS, Morihara T, Teter B,
Ubeda O, Rostaing P, Triller A, Salem N, Ashe
KH, Frautschy SA, Cole GM. Docosahexaenoic
acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43: 633–
645, 2004.
56. Capone R, Quiroz FG, Prangkio P, Saluja I, Sauer
AM, Bautista MR, Turner RS, Yang J, Mayer M.
Amyloid-beta-induced ion flux in artificial lipid
bilayers and neuronal cells: resolving a controversy. Neurotox Res 16: 1–13, 2009.
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
13. Arlt S, Beisiegel U, Kontush A. Lipid peroxidation
in neurodegeneration: new insights into Alzheimer’s disease. Curr Opin Lipid 13: 289 –294,
2002.
25. Baudier J, Cole RD. Phosphorylation of tau-proteins to a state like that in Alzheimers brain is
catalyzed by a calcium calmodulin-dependent kinase and modulated by phospholipids. J Biol
Chem 262: 17577–17583, 1987.
REVIEWS
57. Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, Booze R,
Markesbery WR, Butterfield DA. Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part 1: creatine kinase bb,
glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 33: 562–
571, 2002.
58. Castegna A, Aksenov M, Thongboonkerd V,
Klein JB, Pierce WM, Booze R, Markesbery WR,
Butterfield DA. Proteomic identification of oxidatively modified proteins in Alzheimer’s disease
brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71.
J Neurochem 82: 1524 –1532, 2002.
59. Castegna A, Lauderback CM, Mohmmad-Abdul
H, Butterfield DA. Modulation of phospholipid
asymmetry in synaptosomal membranes by the
lipid peroxidation products, 4-hydroxynonenal
and acrolein: implications for Alzheimer’s disease. Brain Res 1004: 193–197, 2004.
61. Castellani RJ, Perry G, Harris PLR, Cohen ML,
Sayre LM, Salomon RG, Smith MA. Advanced
lipid peroxidation end-products in Alexander’s
disease. Brain Res 787: 15–18, 1998.
62. Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent
bystanders. Ann Rev Neurosci 26: 267–298,
2003.
63. Chauhan A, Ray I, Chauhan VPS. Interaction of
amyloid beta-protein with anionic phospholipids:
possible involvement of Lys(28) and C-terminus
aliphatic amino acids. Neurochem Res 25: 423–
429, 2000.
64. Cherny RA, Atwood CS, Xilinas ME, Gray DN,
Jones WD, Mclean CA, Barnham KJ, Volitakis I,
Fraser FW, Kim YS, Huang XD, Goldstein LE, Moir
RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. Treatment with a copper-zinc
chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30: 665– 676, 2001.
65. Cherny RA, Legg JT, Mclean CA, Fairlie DP,
Huang XD, Atwood CS, Beyreuther K, Tanzi RE,
Masters CL, Bush AI. Aqueous dissolution of Alzheimer’s disease A beta amyloid deposits by biometal depletion. J Biol Chem 274: 23223–23228,
1999.
66. Chi EY, Ege C, Winans A, Majewski J, Wu GH,
Kjaer K, Lee KYC. Lipid membrane templates the
ordering and induces the fibrillogenesis of Alzheimer’s disease amyloid-beta peptide. Proteins
72: 1–24, 2008.
67. Chi EY, Frey SL, Lee KYC. Ganglioside GM1mediated amyloid-beta fibrillogenesis and membrane disruption. Biochemistry 46: 1913–1924,
2007.
68. Choo-Smith LP, Garzon-Rodriguez W, Glabe CG,
Surewicz WK. Acceleration of amyloid fibril formation by specific binding of Abeta-(1-40)
peptide to ganglioside-containing membrane
vesicles. J Biol Chem 272: 22987–22990, 1997.
69. Choo-Smith LP, Surewicz WK. The interaction between Alzheimer amyloid beta(1-40) peptide and
ganglioside GM1-containing membranes. FEBS
Lett 402: 95–98, 1997.
70. Ciccotosto GD, Tew D, Curtain CC, smith D, Carrington D, Masters CL, Bush AI, Cherny RA, Cappai R, Barnham KJ. Enhanced toxicity and cellular
binding of a modified amyloid beta peptide with
a methionine to valine substitution. J Biol Chem
279: 28425– 42538, 2004.
86. Deshpande A, Kawai H, Metherate R, Glabe CG,
Busciglio J. A role for synaptic zinc in activitydependent A beta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:
4004 – 4015, 2009.
72. Cleary JP, Walsh DM, Hofmeister JJ, Shankar
GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural
oligomers of the amyloid-protein specifically disrupt cognitive function. Nat Neurosci 8: 79 – 84,
2005.
87. Devanathan S, Salamon Z, Lindblom G, Grobner
G, Tollin G. Effects of sphingomyelin, cholesterol
and zinc ions on the binding, insertion and aggregation of the amyloid A beta(1-40) peptide in
solid-supported lipid bilayers. FEBS J 273: 1389 –
1402, 2006.
73. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD,
Haines JL, Pericakvance MA. Gene dose of apolipoprotein-E type-4 allele and the risk of Alzheimers-disease in late-onset families. Science
261: 921–923, 1993.
74. Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer’s disease. Mol
Membr Biol 23: 111–122, 2006.
75. Cuajungco MP, Goldstein LE, Nunomura A,
Smith MA, Lim JT, Atwood CS, Huang X, Farrag
YW, Perry G, Bush AI. Evidence that the ␤-amyloid plaques of Alzheimer’s disease represent the
redox-silencing and entombment of abeta by
zinc. J Biol Chem 275: 19439 –19442, 2000.
76. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS,
Beyreuther K, Barrow CJ, Masters CL, Bush AI,
Barnham KJ. Alzheimer’s eisease amyloid-beta
binds copper and zinc to generate an allosterically ordered membrane-penetrating structure
containing superoxide dismutase-like subunits. J
Biol Chem 276: 20466 –20473, 2001.
77. Curtain CC, Ali FE, Smith DG, Bush AI, Masters
CL, Barnham KJ. Metal ions, pH, and cholesterol
regulate the interactions of Alzheimer’s disease
amyloid-beta peptide with membrane lipid. J Biol
Chem 278: 2977–2982, 2003.
78. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP.
Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism
in brain aging and Alzheimer’s disease. Proc Natl
Acad Sci USA 101: 2070 –2075, 2004.
79. D’Errico G, Vitiello G, Ortona O, Tedeschi A,
Ramunno A, D’Ursi AM. Interaction between Alzheimer’s A beta(25-35) peptide and phospholipid
bilayers: the role of cholesterol. Biochim Biophys
Acta 1778: 2710 –2716, 2008.
80. Dalle-Donne I, Rossi R, Giustarini D, Gagliano N,
Lusini L, Milzani A, Di Simplicio P, Colombo R.
Actin carbonylation: from a simple marker of protein oxidation to relevant signs of severe functional impairment. Free Radic Biol Med 31: 1075–
1083, 2001.
81. Dante S, Hauss T, Brandt A, Dencher NA. Membrane fusogenic activity of the Alzheimer’s peptide A beta(1-42) demonstrated by small-angle
neutron scattering. J Mol Biol 376: 393– 404,
2008.
88. Diaz JC, Simakova O, Jacobson KA, Arispe N,
Pollard HB. Small molecule blockers of the Alzheimer A beta calcium channel potently protect
neurons from A beta cytotoxicity. Proc Natl Acad
Sci USA 106: 3348 –3353, 2009.
89. Dikalov SI, Vitek MP, Maples KR, Mason RP. Amyloid beta peptides do not form peptide-derived
free radicals spontaneously, but can enhance
metal-catalyzed oxidation of hydroxylamines to
nitroxides. J Biol Chem 274: 9392–9399, 1999.
90. Donnelly PS, Xiao ZG, Wedd AG. Copper and
Alzheimer’s disease. Curr Opin Chem Biol 11:
128 –133, 2007.
91. Drake J, Link CD, Butterfield DA. Oxidative
stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1-42) in a
transgenic Caenorhabditis elegans model. Neurobiol Aging 24: 415– 420, 2003.
92. Drew SC, Noble CJ, Masters CL, Hanson GR,
Barnham KJ. Pleomorphic copper coordination
by Alzheimer’s disease amyloid-beta peptide. J
Am Chem Soc 131: 1195–1207, 2009.
93. Durell SR, Guy HR, Arispe N, Rojas E, Pollard
HB. Theoretical-models of the ion-channel structure of amyloid beta-protein. Biophys J 67: 2137–
2145, 1994.
94. Ege C, Lee KYC. Insertion of Alzheimer’s A beta
40 peptide into lipid monolayers. Biophys J 87:
1732–1740, 2004.
95. Ehehalt R, Keller P, Haass C, Thiele C, Simons K.
Amyloidogenic processing of the Alzheimer
beta-amyloid precursor protein depends on lipid
rafts. J Cell Biol 160: 113–123, 2003.
96. Eliezer D. Amyloid ion channels: a porous argument or a thin excuse? J Gen Physiol 128: 631–
633, 2006.
97. Esterbauer H, Benedetti A, LANGJ, , Fulceri R,
Fauler G, Comporti M. Studies on the mechanism
of formation of 4-hydroxynonenal during microsomal lipid-peroxidation. Biochim Biophys Acta
876: 154 –166, 1986.
98. Esterbauer H, Schaur RJ, Zollner H. Chemistry
and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol
Med 11: 81–128, 1991.
82. Dante S, Hauss T, Dencher NA. Insertion of externally administered amyloid beta peptide
25-35 and perturbation of lipid bilayers. Biochemistry 42: 13667–13672, 2003.
99. Evans KC, Berger EP, Cho CG, Weisgraber KH,
Lansbury PT. Apolipoprotein E is a kinetic but not
a thermodynamic inhibitor of amyloid formation:
implications for the pathogenesis and treatment
of Alzheimer disease. Proc Natl Acad Sci USA 92:
763–767, 1995.
83. de Planque MRR, Raussens V, Contera SA, Rijkers
DTS, Liskamp RMJ, Ruysschaert JM, Ryan JF, Separovic F, Watts A. beta-sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model
membranes. J Mol Biol 368: 982–997, 2007.
100. Faller P, Hureau C. Bioinorganic chemistry of
copper and zinc ions coordinated to amyloidbeta peptide. Dalton Trans 21: 1080 –1094, 2009.
84. DeMar JC, Ma KZ, Bell JM, Rapoport SI. Halflives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of
nutritional deprivation of n-3 polyunsaturated
fatty acids. J Neurochem 91: 1125–1137, 2004.
85. Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer’s disease. J Biol Chem 285: 12463–12468, 2010.
101. Farooqui AA, Horrocks LA. Plasmalogens: Workhorse lipids of membranes in normal and injured
neurons and glia. Neuroscientist 7: 232–245,
2001.
102. Farooqui AA, Rapoport SI, Horrocks LA. Membrane phospholipid alterations in Alzheimer’s
disease: Deficiency of ethanolamine plasmalogens. Neurochem Res 22: 523–527, 1997.
103. Friedland RP. Fish consumption and the risk of
Alzheimer disease - Is it time to make dietary
recommendations? Arch Neurol 60: 923–924,
2003.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
63
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
60. Castegna A, Thongboonkerd V, Klein JB, Lynn B,
Markesbery WR, Butterfield DA. Proteomic identification of nitrated proteins in Alzheimer’s disease brain. J Neurochem 85: 1394 –1401, 2003.
71. Cirrito JR, Yamada KA, Finn MB, Sloviter RS,
Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates
interstitial fluid amyloid-beta levels in vivo. Neuron 48: 913–922, 2005.
REVIEWS
104. Galbusera C, Facheris M, Magni F, Galimberti G,
Sala G, Tremolada L, Isella V, Guerini FR, Appollonio I, Galli-Kienle M, Ferrarese C. Increased
susceptibility to plasma lipid peroxidation in Alzheimer disease patients. Curr Alzheimer Res 1:
103–109, 2004.
105. Garzon-Rodriguez W, Yatsimirsky AK, Glabe CG.
Binding of Zn(II), Cu(II), and Fe(II) ions to Alzheimer’s A beta peptide studied by fluorescence.
Bioorg Med Chem Lett 9: 2243–2248, 1999.
106. Gehman JD, O’Brien CC, Shabanpoor F, Wade
JD, Separovic F. Metal effects on the membrane
interactions of amyloid-beta peptides. Eur Biophys J Biophys Lett 37: 333–344, 2008.
107. Ghezzi P, Bonetto V. Redox proteomics: Identification of oxidatively, modified proteins. Proteomics 3: 1145–1153, 2003.
109. Giles GI, Jacob C. Reactive sulfur species: an
emerging concept in oxidative stress. Biol Chem
383: 375–388, 2002.
110. Ginsberg L, Rafique S, Xuereb JH, Rapoport SI,
Gershfeld NL. Disease and anatomic specificity
of ethanolamine plasmalogen deficiency in Alzheimers-disease brain. Brain Res 698: 223–226,
1995.
111. Ginsberg L, Xuereb JH, Gershfeld NL. Membrane instability, plasmalogen content, and Alzheimer’s disease. J Neurochem 70: 2533–2538,
1998.
112. Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PWK, Heath D, Yamazaki
Y, Flax J, Krenitsky KF, Sparks DL, Lerner A,
Friedland RP, Kudo T, Kamino K, Morihara T,
Takeda M, Wood PL. Peripheral ethanolamine
plasmalogen deficiency: a logical causative factor
in Alzheimer’s disease and dementia. J Lipid Res
48: 2485–2498, 2007.
113. Gorbenko GP, Kinnunen PKJ. The role of lipidprotein interactions in amyloid-type protein fibril
formation. Chem Phys Lipids 141: 72– 82, 2006.
114. Green JD, Kreplak L, Goldsbury C, Blatter XL,
Stolz M, Cooper GS, Seelig A, Kist-Ler J, Aebi U.
Atomic force microscopy reveals defects within
mica supported lipid bilayers induced by the
amyloidogenic human amylin peptide. J Mol Biol
342: 877– 887, 2004.
122. Hansen LM, Masliah E, Galasko D, Terry RD.
Plaque-only Alzheimer-disease is usually the
Lewy body variant, and vice-versa. J Neuropath
Exp Neurol 52: 648 – 654, 1993.
123. Hardy J, Allsop D. Amyloid deposition as the
central event in the etiology of Alzheimers-disease. Trends Pharmacol Sci 12: 383–388, 1991.
124. Hardy JA, Higgins GA. Alzheimers-disease: the
amyloid cascade hypothesis. Science 256: 184 –
185, 1992.
125. Harper JD, Wong SS, Lieber CM, Lansbury PT.
Observation of metastable A beta amyloid
protofibrils by atomic force microscopy. Chem
Biol 4: 119 –125, 1997.
126. Hashimoto M, Tanabe Y, Fujii Y, Kikuta T, Shibata
H, Shido O. Chronic administration of docosahexaenoic acid ameliorates the impairment of
spatial cognition learning ability in amyloid betainfused rats. J Nutr 135: 549 –555, 2005.
127. Hayashi H, Kimura N, Yamaguchi H, Hasegawa K,
Yokoseki T, Shibata M, Yamamoto N, Michikawa
M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere
CA, Selkoe DJ, Naiki H, Yanagisawa K. A seed for
Alzheimer amyloid in the brain. J Neurosci 24:
4894 – 4902, 2004.
128. Hensley K, Carney JM, Mattson MP, Aksenova
M, Harris M, Wu JF, Floyd RA, Butterfield DA. A
model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the
peptide: relevance to Alzheimer disease. Proc
Natl Acad Sci USA 91: 3270 –3274, 1994.
129. Hensley K, Hall N, Subramaniam R, Cole P, Harris
M, Aksenov M, Aksenova M, Gabbita SP, Wu JF,
Carney JM, Lovell MA, Markesbery WR, Butterfield DA. Brain regional correspondence between Alzheimers-disease histopathology and
biomarkers of protein oxidation. J Neurochem
65: 2146 –2156, 1995.
130. Hertel C, Terzi E, Hauser N, Jakob-Rotne R,
Seelig J, Kemp JA. Inhibition of the electrostatic
interaction between beta-amyloid peptide and
membranes prevents beta-amyloid-induced toxicity. Proc Natl Acad Sci USA 94: 9412–9416,
1997.
136. Hung LW, Ciccotosto GD, Giannakis E, Tew DJ,
Perez K, Masters CL, Cappai R, Wade JD, Barnham KJ. Amyloid-beta peptide (A beta) neurotoxicity is modulated by the rate of peptide
aggregation: A beta dimers and trimers correlate
with neurotoxicity. J Neurosci 28: 11950 –11958,
2008.
137. Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman
CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB,
Frosch MP, Windisch M, Kovacs DM. The ACAT
inhibitor CP-113,818 markedly reduces amyloid
pathology in a mouse model of Alzheimer’s disease. Neuron 44: 227–238, 2004.
138. Igarashi M, Gao F, Kim HW, Ma KZ, Bell JM,
Rapoport SI. Dietary n-6 PUFA deprivation for 15
weeks reduces arachidonic acid concentrations
while increasing n-3 PUFA concentrations in organs of post-weaning male rats. BBA Mol Cell
Biol Lipids 1791: 132–139, 2009.
139. Inoue K, Garner C, Ackermann BL, Oe T, Blair IA.
Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta
peptides as potential biomarkers of Alzheimer’s
disease. Rapid Commun Mass Spectrom 20: 911–
918, 2006.
140. Isaacs AM, Senn DB, Yuan M, Shine JP, Yankner
BA. Acceleration of amyloid beta -peptide aggregation by physiological concentrations of calcium. J Biol Chem 281: 27916 –27923, 2006.
141. Issa AM, Mojica WA, Morton SC, Traina S, Newberry SJ, Hilton LG, Garland RH, MacLean CH.
The efficacy of omega-3 fatty acids on cognitive
function in aging and dementia: a systematic review. Dement Geriatr Cogn Disord 21: 88 –96,
2006.
142. Jang H, Arce FT, Ramachandran S, Capone R,
Azimova R, Kagan BL, Nussinov R, Lal R. Truncated ␤-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and
Down syndrome. Proc Natl Acad Sci USA 107:
6838 – 6543, 2010.
143. Jarrett JT, Berger EP, Lansbury PT. The carboxy
terminus of the beta amyloid protein is critical for
the seeding of amyloid formation: implications
for the pathogenesis of Alzheimer’s disease. Biochemistry 32: 4693– 4697, 1993.
144. Jeandel C, Nicolas MB, Dubois F, Nabet-Belleville F, Penin F, Cuny G. Lipid peroxidation and
free radical scavengers in Alzheimer’s disease.
Gerontology 35: 275–282, 1989.
115. Gylys KH, Fein JA, Yang F, Miller CA, Cole GM.
Increased cholesterol in A beta-positive nerve
terminals from Alzheimer’s disease cortex. Neurobiol Aging 28: 8 –17, 2007.
131. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell
RL, Atwood CS, Johnson AB, Kress Y, Vinters HV,
Tabaton M, Shimohama S, Cash AD, Siedlak SL,
Harris PLR, Jones PK, Petersen RB, Perry G,
Smith MA. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21: 3017–3023, 2001.
145. Ji SR, Wu Y, Sui SF. Cholesterol is an important
factor affecting the membrane insertion of betaamyloid peptide (A beta 1-40), which may potentially inhibit the fibril formation. J Biol Chem 277:
6273– 6279, 2002.
116. Haeffner F, Smith DG, Barnham KJ, Bush AI.
Model studies of cholesterol and ascorbate oxidation by copper complexes: relevance to Alzheimer’s disease beta-amyloid metallochemistry.
J Inorg Biochem 99: 2403–2422, 2005.
132. Hou LM, Kang I, Marchant RE, Zagorski MG.
Methionine 35 oxidation reduces fibril assembly
of the amyloid A beta-(1-42) peptide of Alzheimer’s disease. J Biol Chem 277: 40173– 40176,
2002.
117. Hahnel D, Beyer K, Engelmann B. Inhibition of
peroxyl radical-mediated lipid oxidation by plasmalogen phospholipids and alpha-tocopherol.
Free Radic Biol Med 27: 1087–1094, 1999.
133. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T,
Sisodia S, Malinow R. AMPAR removal underlies
A beta-induced synaptic depression and dendritic spine loss. Neuron 52: 831– 843, 2006.
146. Johansson AS, Garlind A, Berglind-Dehlin F,
Karlsson G, Edwards K, Gellerfors P, EkholmPettersson F, Palmblad J, Lannfelt L. Docosahexaenoic acid stabilizes soluble amyloid-beta
protofibrils and sustains amyloid-beta-induced
neurotoxicity in vitro. FEBS J 274: 990 –1000,
2007.
118. Hahnel D, Huber T, Kurze V, Beyer K, Engelmann
B. Contribution of copper binding to the inhibition of lipid oxidation by plasmalogen phospholipids. Biochem J 340: 377–383, 1999.
134. Huang XD, Atwood CS, Hartshorn MA, Multhaup
G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray
DN, Lim J, Moir RD, Tanzi RE, Bush AI. The A
beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38: 7609 –7616, 1999.
119. Han X. Lipid alterations in the earliest clinically
recognizable stage of Alzheimer’s disease: implication of the role of lipids in the pathogenesis of
Alzheimer’s disease. Curr Alzheimer Res 2: 65–
77, 2005.
120. Han XL, Holtzman DM, McKeel DW. Plasmalogen
deficiency in early Alzheimer’s disease subjects
and in animal models: molecular characterization
using electrospray ionization mass spectrometry.
J Neurochem 77: 1168 –1180, 2001.
64
135. Huang XD, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JDA, Hanson GR, Stokes KC,
Leopold M, Multhaup G, Goldstein LE, Scarpa
RC, Saunders AJ, Lim J, Moir RD, Glabe C,
Bowden EF, Masters CL, Fairlie DP, Tanzi RE,
Bush AI. Cu(II) potentiation of Alzheimer A beta
neurotoxicity: correlation with cell-free hydrogen
peroxide production and metal reduction. J Biol
Chem 274: 37111–37116, 1999.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
147. Kagan BL, Azimov R, Azimova R. Amyloid peptide channels. J Membrane Biol 202: 1–10, 2004.
148. Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi
Y, Matsuzaki K. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid betaprotein, an endogenous seed for Alzheimer
amyloid. J Biol Chem 276: 24985–24990, 2001.
149. Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi
Y, Matsuzaki K. Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound
form as an endogenous seed for Alzheimer amyloid. Biochemistry 41: 7385–7390, 2002.
150. Kakio A, Nishimoto SI, Kozutsumi Y, Matsuzaki K.
Formation of a membrane-active form of amyloid
beta-protein in raft-like model membranes.
Biochem Biophys Res Commun 303: 514 –518,
2003.
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
108. Ghribi O, Larsen B, Schrag M, Herman MM. High
cholesterol content in neurons increases BACE,
beta-amyloid, and phosphorylated tau levels in
rabbit hippocampus. Exp Neurol In Press: 2006.
121. Han XL, Holtzman DM, McKeel DW, Kelley J,
Morris JC. Substantial sulfatide deficiency and
ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J
Neurochem 82: 809 – 818, 2002.
REVIEWS
151. Kakio A, Yano Y, Takai D, Kuroda Y, Matsumoto
O, Kozutsumi Y, Matsuzaki K. Interaction between amyloid beta-protein aggregates and
membranes. J Pept Sci 10: 612– 621, 2004.
152. Kalvodova L, Kahya N, Schwille P, Ehehalt R,
Verkade P, Drechsel D, Simons K. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and
anionic phospholipids in vitro. J Biol Chem 280:
36815–36823, 2005.
153. Karr JW, Szalai VA. Cu(II) binding to monomeric,
oligomeric, and fibrillar forms of the Alzheimer’s
disease amyloid-beta peptide. Biochemistry 47:
5006 –5016, 2008.
154. Kayed R, Sokolov Y, Edmonds B, McIntire TM,
Milton SC, Hall JE, Glabe CG. Permeabilization of
lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279:
46363– 46366, 2004.
156. Khaselev N, Murphy RC. Susceptibility of plasmenyl glycerophosphoethanolamine lipids containing arachidonate to oxidative degradation. Free
Radic Biol Med 26: 275–284, 1999.
157. Khaselev N, Murphy RC. Peroxidation of arachidonate containing plasmenyl glycerophosphocholine: facile oxidation of esterified arachidonate at
carbon-5. Free Radic Biol Med 29: 620 – 632,
2000.
158. Khaselev N, Murphy RC. Structural characterization of oxidized phospholipid products derived
from arachidonate-containing plasmenyl glycerophosphocholine. J Lipid Res 41: 564 –572, 2000.
159. Kim HY. Novel metabolism of docosahexaenoic
acid in neural cells. J Biol Chem 282: 18661–
18665, 2007.
160. Kitazawa M, Cheng D, LaFerla FM. Chronic copper exposure exacerbates both amyloid and tau
pathology and selectively dysregulates cdk5 in a
mouse model of AD. J Neurochem 108: 1550 –
1560, 2009.
161. Komatsu H, Liu L, Murray IV, Axelsen PH. A
mechanistic link between oxidative stress and
membrane mediated amyloidogenesis revealed
by infrared spectroscopy. BBA Biomembranes
1768: 1913–1922, 2007.
162. Kontush A. Amyloid-␤: an antioxidant that becomes a pro-oxidant and critically contributes to
Alzheimer’s disease. Free Radic Biol Med 31:
1120 –1131, 2001.
163. Kontush A, Berndt C, Weber W, Akopyan V, Arlt
S, Schippling S, Beisiegel U. Amyloid-␤ is an antioxidant for lipoproteins in cerebrospinal fluid
and plasma. Free Radic Biol Med 30: 119 –128,
2001.
164. Kontush A, Donarski N, Beisiegel U. Resistance
of human cerebrospinal fluid to in vitro oxidation
is directly related to its amyloid-beta content.
Free Radic Res 35: 507–517, 2001.
165. Koppaka V, Axelsen PH. Accelerated accumulation of amyloid beta proteins on oxidatively damaged lipid membranes. Biochemistry 39: 10011–
10016, 2000.
166. Koppaka V, Paul C, Murray IVJ, Axelsen PH. Early
synergy between A␤42 and oxidatively damaged
membranes in promoting amyloid fibril formation
by A␤40. J Biol Chem 278: 36277–36284, 2003.
167. Kremer JJ, Murphy RM. Kinetics of adsorption of
beta-amyloid peptide A beta(1-40) to lipid bilayers. J Biochem Biophys Methods 57: 159 –169,
2003.
169. Kremer JJ, Sklansky DJ, Murphy RM. Profile of
changes in lipid bilayer structure caused by betaamyloid peptide. Biochemistry 40: 8563– 8571,
2001.
170. Kuczynski B, Reo NV. Evidence that plasmalogen
is protective against oxidative stress in the rat
brain. Neurochem Res 31: 639 – 656, 2006.
171. Ladu MJ, Falduto MT, Manelli AM, Reardon CA,
Getz GS, Frail DE. Isoform-specific binding of
apolipoprotein-E to beta-amyloid. J Biol Chem
269: 23403–23406, 1994.
172. LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev
Neurosci 3: 862– 872, 2002.
173. Lal R, Lin H, Quist AP. Amyloid beta ion channel: 3D
structure and relevance to amyloid channel paradigm. BBA Biomembranes 1768: 1966–1975, 2007.
174. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury
PT. Neurodegenerative disease: amyloid pores
from pathogenic mutations. Nature 418: 291,
2002.
175. Lashuel HA, Lansbury PT. Are amyloid diseases
caused by protein aggregates that mimic bacterial pore-forming toxins? Q Rev Biophys 39: 167–
201, 2006.
176. Lau TL, Ambroggio EE, Tew DJ, Cappai R, Masters CL, Fidelio GD, Barnham KJ, Separovic F.
Amyloid-beta peptide disruption of lipid membranes and the effect of metal ions. J Mol Biol
356: 759 –770, 2006.
177. Lauderback CM, Hackett JM, Huang FF, Keller
JN, Szweda LI, Markesbery WR, Butterfield DA.
The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the
Alzheimer’s disease brain: the role of A beta
1– 42. J Neurochem 78: 413– 416, 2001.
178. Lauderback CM, Kanski J, Hackett JM, Maeda N,
Kindy MS, Butterfield DA. Apolipoprotein E modulates Alzheimer’s A beta(1-42)-induced oxidative damage to synaptosomes in an allele-specific
manner. Brain Res 924: 90 –97, 2002.
179. Lawson JA, Rokach J, FitzGerald GA. Isoprostanes: formation, analysis and use as indices of
lipid peroxidation in vivo. J Biol Chem 274:
24441–24444, 1999.
186. Lin H, Bhatia R, Lal R. Amyloid beta protein forms
ion channels: implications for Alzheimer’s disease
pathophysiology. FASEB J 15: 2433–2444, 2001.
187. Liu L, Komatsu H, Murray IVJ, Axelsen PH. Promotion of amyloid ␤ protein misfolding and fibrillogenesis by a lipid oxidation product. J Mol Biol
377: 1236 –1250, 2008.
188. Liu SJ, Zukin RS. Ca2⫹-permeable AMPA receptors in synaptic plasticity and neuronal death.
Trends Neurosci 30: 126 –134, 2007.
189. Lorenzo A, Yuan ML, Zhang ZH, Paganetti PA,
Sturchler-Pierrat C, Staufenbiel M, Mautino J, Sol
V, Sommer B, Yankner BA. Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat
Neurosci 3: 460 – 464, 2000.
190. Lovell MA, Ehmann WD, Mattson MP, Markesbery WR. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol Aging
18: 457– 461, 1997.
191. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in
Alzheimer’s disease senile plaques. J Neurol Sci
158: 47–52, 1998.
192. Lovell MA, Xie CS, Markesbery WR. Acrolein is
increased in Alzheimer’s disease brain and is
toxic to primary hippocampal cultures. Neurobiol
Aging 22: 187–194, 2001.
193. Lukiw WJ, Cui JG, Marcheselli VL, Bodker M,
Botkjaer A, Gotlinger K, Serhan CN, Bazan NG. A
role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer
disease. J Clin Invest 115: 2774 –2783, 2005.
194. Ma JY, Yee A, Brewer HB, Das S, Potter H. Amyloid-associated proteins alpha(1)-antichymotrypsin and apolipoprotein-E promote assembly
of Alzheimer beta-protein into filaments. Nature
372: 92–94, 1994.
195. Maeba R, Sawada Y, Shimasaki H, Takahashi I,
Ueta N. Ethanolamine plasmalogens protect cholesterol-rich liposomal membranes from oxidation caused by free radicals. Chem Phys Lipids
120: 145–151, 2002.
196. Maeba R, Ueta N. Ethanolamine plasmalogens
prevent the oxidation of cholesterol by reducing
the oxidizability of cholesterol in phospholipid
bilayers. J Lipid Res 44: 164 –171, 2003.
197. Mahley RW, Rall SC Jr. Apolipoprotein E: far
more than a lipid transport protein. Ann Rev
Genom Hum Gen 1: 507–537, 2000.
180. Lee SH, Blair IA. Characterization of 4-oxo-2-nonenal as a novel product of lipid peroxidation.
Chem Res Tox 13: 698 –702, 2000.
198. Manelli AM, Stine WB, Van Eldik LJ, Ladu MJ.
ApoE A␤1– 42 interactions. J Mol Neurosci 23:
235–246, 2004.
181. Lee SJ, Liyanage U, Bickel PE, Xia WM, Lansbury
PT, Kosik KS. A detergent-insoluble membrane
compartment contains A beta in vivo. Nat Med 4:
730 –734, 1998.
199. Marchesi VT. An alternative interpretation of the
amyloid A beta hypothesis with regard to the
pathogenesis of Alzheimer’s disease. Proc Natl
Acad Sci USA 102: 9093–9098, 2005.
182. Lehtonen JYA, Holopainen JM, Kinnunen PKJ. Activation of phospholipase A(2) by amyloid betapeptides in vitro. Biochemistry 35: 9407–9414,
1996.
200. Marcus DL, Thomas C, Rodriguez C, Simberkoff
K, Tsai JS, Strafaci JA, Freedman ML. Increased
peroxidation and reduced antioxidant enzyme
activity in Alzheimer’s disease. Exp Neurol 150:
40 – 44, 1998.
183. Leskovjan AC, Lanzirotti A, Miller LM. Amyloid
plaques in PSAPP mice bind less metal than
plaques in human Alzheimer’s disease. Neuroimage 47: 1215–1220, 2009.
184. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG,
Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs
memory. Nature 440: 352–357, 2006.
185. Lim GP, Calon F, Morihara T, Yang FS, Teter B,
Ubeda O, Salem N, Frautschy SA, Cole GM. A
diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an
aged Alzheimer mouse model. J Neurosci 25:
3032–3040, 2005.
201. Markesbery WR. Oxidative stress hypothesis in
Alzheimer’s disease. Free Radic Biol Med 23:
134 –147, 1997.
202. Markesbery WR, Carney JM. Oxidative alterations in Alzheimer’s disease. Brain Pathol 9: 133–
146, 1999.
203. Markesbery WR, Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased
in the brain in Alzheimer’s disease. Neurobiol
Aging 19: 33–36, 1998.
204. Martinez-Senac MD, Villalain J, Gomez-Fernandez JC. Structure of the Alzheimer beta-amyloid
peptide (25-35) and its interaction with negatively charged phospholipid vesicles. Eur J
Biochem 265: 744 –753, 1999.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
65
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
155. Kelly BL, Ferreira A. Beta-amyloid-induced dynamin 1 degradation is mediated by N-methyl-Daspartate receptors in hippocampal neurons. J
Biol Chem 281: 28079 –28089, 2006.
168. Kremer JJ, Pallitto MM, Sklansky DJ, Murphy
RM. Correlation of ␤-amyloid aggregate size and
hydrophobicity with decreased bilayer fluidity of
model membranes. Biochemistry 39: 10309 –
10318, 2000.
REVIEWS
205. Matsuzaki K. Physicochemical interactions of amyloid ␤-peptide with lipid bilayers. BBA
Biomembranes 1768: 1935–1942, 2007.
206. Matsuzaki K, Horikiri C. Interactions of amyloid
beta-peptide (1-40) with ganglioside-containing
membranes. Biochemistry 38: 4137– 4142, 1999.
207. Matsuzaki K, Noguch T, Wakabayashi M, Ikeda K,
Okada T, Ohashi Y, Hoshino M, Naiki H. Inhibitors of amyloid beta-protein aggregation mediated by GM1-containing raft-like membranes.
BBA Biomembranes 1768: 122–130, 2007.
208. Mattson MP, Cheng B, Culwell AR, Esch FS,
Lieberburg I, Rydel RE. Evidence for excitoprotective and intraneuronal calcium-regulating
roles for secreted forms of the beta-amyloid precursor protein. Neuron 10: 243–254, 1993.
210. McGrath LT, McGleenon BM, Brennan S, McColl
D, McIlroy S, Passmore AP. Increased oxidative
stress in Alzheimer’s disease as assessed with
4-hydroxynonenal but not malondialdehyde.
QJM 94: 485– 490, 2001.
211. McIntosh LJ, Trush MA, Troncoso JC. Increased
susceptibility of Alzheimer’s disease temporal
cortex to oxygen free radical-mediated processes. Free Radic Biol Med 23: 183–190, 1997.
212. McLaurin J, Chakrabartty A. Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific finding to either
phospholipids or gangliosides: implications for
neurotoxicity. J Biol Chem 271: 26482–26489,
1996.
213. McLaurin J, Chakrabartty A. Characterization of
the interactions of Alzheimer beta-amyloid peptides with phospholipid membranes. Eur J
Biochem 245: 355–363, 1997.
214. McLaurin J, Darabie AA, Morrison MR. Cholesterol, a modulator of membrane-associated A
beta-fibrillogenesis. Alz Dis Vasc Etiol Path 977:
376 –383, 2002.
215. McLaurin J, Franklin T, Fraser PE, Chakrabartty
A. Structural transitions associated with the interaction of Alzheimer beta-amyloid peptides
with gangliosides. J Biol Chem 273: 4506 – 4515,
1998.
216. Minton AP. Implications of macromolecular
crowding for protein assembly. Curr Opin Struct
Biol 10: 34 –39, 2000.
217. Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid
peptides. Nat Gen 14: 55– 61, 1996.
218. Molander-Melin M, Blennow K, Bogdanovic N,
Dellheden B, Mansson JE, Fredman P. Structural
membrane alterations in Alzheimer brains found
to be associated with regional disease development; increased density of gangliosides GM1
and GM2 and loss of cholesterol in detergentresistant membrane domains. J Neurochem 92:
171–182, 2005.
219. Monji A, Utsumi H, Ueda T, Imoto T, Yoshida I,
Hashioka S, Tashiro K, Tashiro N. The relationship between the aggregational state of the amyloid-beta peptides and free radical generation
by the peptides. J Neurochem 77: 1425–1432,
2001.
220. Montine TJ, Neely MD, Quinn JF, Beal MF,
Markesbery WR, Roberts LJ, Morrow JD. Lipid
peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol Med 33: 620 – 626, 2002.
221. Montine TJ, Quinn JF, Milatovic D, Silbert LC,
Dang T, Sanchez S, Terry E, Roberts LJ, Kaye JA,
Morrow JD. Peripheral F-2-isoprostanes and F-4neuroprostanes are not increased in Alzheimer’s
disease. Ann Neurol 52: 175–179, 2002.
66
223. Morris MC, Evans DA, Bienias JL, Tangney CC,
Bennett DA, Wilson RS, Aggarwal N, Schneider J.
Consumption of fish and n-3 fatty acids and risk
of incident Alzheimer disease. Arch Neurol 60:
940 –946, 2003.
224. Morris MC, Evans DA, Tangney CC, Bienias JL,
Wilson RS. Fish consumption and cognitive decline with age in a large community study. Arch
Neurol 62: 1849 –1853, 2005.
225. Morrow JD, Awad JA, Boss HJ, Blair IA, Roberts
LJ, II. Non-cyclooxygenase-derived prostanoids
(F2-Isoprostanes) are formed in situ on phosphlipids. Proc Natl Acad Sci USA 89: 10721–10725,
1992.
226. Morrow JD, Minton TA, Mukundan CR, Campbell
MD, Zackert WE, Daniel VC, Badr KF, Blair IA,
Roberts LJ II. Free radical-induced generation of
isoprostanes in vivo. J Biol Chem 269: 4317–
4326, 1994.
227. Mulder C, Wahlund LO, Teerlink T, Blomberg M,
Veerhuis R, van Kamp GJ, Scheltens P, Scheffer
PG. Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer’s disease. J Neural Transm 110: 949 –955,
2003.
228. Munishkina LA, Cooper EM, Uversky VN, Fink
AL. The effect of macromolecular crowding on
protein aggregation and amyloid fibril formation.
J Mol Recognit 17: 456 – 464, 2004.
229. Murphy EJ, Huang HM, Cowburn RF, Lannfeltd L,
Gibson GE. Phospholipid mass is increased in
fibroblasts bearing the Swedish amyloid precursor mutation. Brain Res Bull 69: 79 – 85, 2006.
230. Murphy RC. Free-radical-induced oxidation of
arachidonoyl plasmalogen phospholipids: antioxidant mechanism and precursor pathway for bioactive eicosanoids. Chem Res Tox 14: 463– 472,
2001.
231. Murray IVJ, Liu L, Komatsu H, Uryu K, Xiao G,
Lawson JA, Axelsen PH. Membrane mediated
amyloidogenesis and the promotion of oxidative
lipid damage by amyloid beta proteins. J Biol
Chem 282: 9335–9345, 2007.
238. O’Nuallain B, Shivaprasad S, Kheterpal I, Wetzel
R. Thermodynamics of A beta(1-40) amyloid fibril
elongation. Biochemistry 44: 12709–12718, 2005.
239. Okada T, Ikeda K, Wakabayashi M, Ogawa M,
Matsuzaki K. Formation of toxic A beta(1-40) fibrils on GM1 ganglioside-containing membranes
mimicking lipid rafts: polymorphisms in A beta(140) fibrils. J Mol Biol 382: 1066 –1074, 2008.
240. Okada T, Wakabayashi M, Ikeda K, Matsuzaki
K. Formation of toxic fibrils of Alzheimer’s amyloid beta-protein-(1-40) by monosialoganglioside
GM1, a neuronal membrane component. J Mol
Biol 371: 481– 489, 2007.
241. Opazo C, Huang XD, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi
RE, Inestrosa NC, Bush AI. Metalloenzyme-like
activity of Alzheimer’s disease beta-amyloid- Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic
H2O2. J Biol Chem 277: 40302–40308, 2002.
242. Paltauf F. Ether lipids in biomembranes. Chem
Phys Lipids 74: 101–139, 1994.
243. Pamplona R, Dalfo E, Ayala VR, Bellmunt MJ, Prat
J, Ferrer I, Portero-Otin M. Proteins in human
brain cortex are modified by oxidation, glycoxidation, and lipoxidation: effects of Alzheimer disease and identification of lipoxidation targets. J
Biol Chem 280: 21522–21530, 2005.
244. Patrono C, FitzGerald GA. Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 17:
2309 –2315, 1997.
245. Permanne B, Perez C, Soto C, Frangione B, Wisniewski T. Detection of apolipoprotein E dimeric
soluble amyloid beta complexes in Alzheimer’s
disease brain supernatants. Biochem Biophys Res
Commun 240: 715–720, 1997.
246. Petersen CAH, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A,
Winblad B, Glaser E, Ankarcrona M. The amyloid
beta-peptide is imported into mitochondria via
the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 105:
13145–13150, 2008.
247. Pettegrew JW, Panchalingam K, Hamilton RL,
McClure RJ. Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res
26: 771–782, 2001.
232. Murray IVJ, Sindoni ME, Axelsen PH. Promotion
of oxidative lipid membrane damage by amyloid
beta proteins. Biochemistry 44: 12606 –12613,
2005.
248. Pike CJ, RamezanArab N, Cotman CW. Betaamyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants. J
Neurochem 69: 1601–1611, 1997.
233. Namba Y, Tomonaga M, Kawasaki H, Otomo E,
Ikeda K. Apolipoprotein-E immunoreactivity in
cerebral amyloid deposits and neurofibrillary tangles in Alzheimers-disease and Kuru plaque amyloid In Creutzfeldt-Jakob disease. Brain Res 541:
163–166, 1991.
249. Pillot T, Goethals M, Vanloo B, Talussot C, Brasseur R, Vandekerckhove J, Rosseneu M, Lins L.
Fusogenic properties of the C-terminal domain
of the Alzheimer beta-amyloid peptide. J Biol
Chem 271: 28757–28765, 1996.
234. Natte R, Yamaguchi H, Maat-Schieman MLC,
Prins FA, Neeskens P, Roos RAC, van Duinen SG.
Ultrastructural evidence of early non-fibrillar A
beta 42 in the capillary basement membrane of
patients with hereditary cerebral hemorrhage
with amyloidosis, Dutch type. Acta Neuropathol
(Berl) 98: 577–582, 1999.
235. Nelson TJ, Alkon DL. Oxidation of cholesterol by
amyloid precursor protein and beta-amyloid peptide. J Biol Chem 280: 7377–7387, 2005.
236. Nunomura A, Perry G, Pappolla MA, Friedland
RP, Hirai K, Chiba S, Smith MA. Neuronal oxidative stress precedes amyloid-beta deposition in
Down syndrome. J Neuropath Exp Neurol 59:
1011–1017, 2000.
237. Nurk E, Drevon CA, Refsum H, Solvoll K, Vollset
SE, Nygard O, Nygaard HA, Engedal K, Tell GS,
Smith AD. Cognitive performance among the elderly and dietary fish intake: the Hordaland
Health Study. Am J Clin Nutr 86: 1470 –1478,
2007.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
250. Plourde M, Fortier M, Vandal M, TremblayMercier J, Freemantle E, Begin M, Pifferi F,
Cunnane SC. Unresolved issues in the link between docosahexaenoic acid and Alzheimer’s
disease. Prost Leuk Essen Fatty Acids 77: 301–
308, 2007.
251. Pollard HB, Arispe N, Rojas E. Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity. Cell Molec Neurobiol 15: 513–526, 1995.
252. Prasad MR, Lovell MA, Yatin M, Dhillon H,
Markesbery WR. Regional membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res 23: 81– 88, 1998.
253. Pratico D, Clark CM, Lee VMY, Trojanowski JQ,
Rokach J, FitzGerald GA. Increased 8,12-isoiPF(2 alpha)-VI in Alzheimer’s disease: correlation
of a noninvasive index of lipid peroxidation with
disease severity. Ann Neurol 48: 809 – 812, 2000.
254. Pratico D, Delanty N. Oxidative injury in diseases
of the central nervous system: focus on Alzheimer’s disease. Am J Med 109: 577–585, 2000.
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
209. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. ␤-Amyloid peptides destabilize
calcium homeostasis and render human cortical
neurons vulnerable to excitotoxicity. J Neurosci
12: 376 –389, 1992.
222. Morandat S, Bortolato M, Anker G, Doutheau A,
Lagarde M, Chauvet JP, Roux B. Plasmalogens
protect unsaturated lipids against UV-induced
oxidation in monolayer. Biochim Biophys Acta
1616: 137–146, 2003.
REVIEWS
255. Pratico D, Lee VMY, Trojanowski JQ, Rokach J,
FitzGerald GA. Increased F-2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid
peroxidation in vivo. FASEB J 12: 1777–1783,
1998.
256. Pratico D, Uryu K, Leight S, Trojanowswki JQ, Lee
VMY. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of
Alzheimer amyloidosis. J Neurosci 21: 4183–
4187, 2001.
257. Puglielli L, Friedlich AL, Setchell KDR, Nagano S,
Opazo C, Cherny RA, Barnham KJ, Wade JD,
Melov S, Kovacs DM, Bush AI. Alzheimer disease
␤-amyloid activity mimics cholesterol oxidase. J
Clin Invest 115: 2556 –2563, 2005.
258. Qahwash IM, Boire A, Lanning J, Krausz T, Pytel
P, Meredith SC. Site-specific effects of peptide
lipidation on beta-amyloid aggregation and cytotoxicity. J Biol Chem 282: 36987–36997, 2007.
260. Rajendran L, Schneider A, Schlechtingen G,
Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz
JB, Schroeder C, Simons M, Jennings G, Knolker
HJ, Simons K. Efficient inhibition of the Alzheimer’s disease ␤-secretase by membrane targeting. Science 320: 520 –523, 2008.
261. Rangachari V, Moore BD, Reed DK, Sonoda LK,
Bridges AW, Conboy E, Hartigan D, Rosenberry
TL. Amyloid-␤(1-42) rapidly forms protofibrils
and oligomers by distinct pathways in low concentrations of sodium dodecylsulfate. Biochemistry 46: 12451–12462, 2007.
262. Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 218: 286 –292, 2009.
263. Refolo LM, Pappolla MA, Malester B, LaFrancois
J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K. Hypercholesterolemia accelerates
the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7: 321–331,
2000.
264. Reiss D, Beyer K, Engelmann B. Delayed oxidative degradation of polyunsaturated diacyl phospholipids in the presence of plasmalogen
phospholipids in vitro. Biochem J 323: 807– 814,
1997.
265. Relini A, Cavalleri O, Rolandi R, Gliozzi A. The
two-fold aspect of the interplay of amyloidogenic
proteins with lipid membranes. Chem Phys Lipids
158: 1–9, 2009.
266. Roberts LJ, Fessel JP. The biochemistry of the
isoprostane, neuroprostane, and isofuran pathways of lipid peroxidation. Chem Phys Lipids
128: 173–186, 2004.
267. Roberts LJ, Montine TJ, Markesbery WR, Tapper
AR, Hardy P, Chemtob S, Dettbarn WD, Morrow
JD. Formation of isoprostane-like compounds
(neuroprostanes) in vivo from docosahexaenoic
acid. J Biol Chem 273: 13605–13612, 1998.
268. Roberts LJ, II, Morrow JD. IsoProstanes: novel
markers of endogenous lipid peroxidation and
potential mediators of oxidant injury. Ann NY
Acad Sci 744: 237–242, 1994.
269. Roheim PS, Carey M, Forte T, Vega GL. Apolipoproteins in human cerebrospinal fluid. Proc Natl
Acad Sci USA 76: 4646 – 4649, 1979.
270. Rottkamp CA, Nunomura A, Raina AK, Sayre LM,
Perry G, Smith MA. Oxidative stress, antioxidants, and Alzheimer disease. Alzheimer Dis Assoc Disord 14, Suppl 1: S62–S66, 2000.
272. Sarell CJ, Syme CD, Rigby SEJ, Viles JH. Copper(II)
binding to amyloid-beta fibrils of Alzheimer’s disease reveals a picomolar affinity: stoichiometry
and coordination geometry are independent of A
beta oligomeric form. Biochemistry 48: 4388 –
4402, 2009.
285. Shin SJ, Lee SE, Boo JH, Kim M, Yoon YD, Kim SI,
Mook-Jung I. Profiling proteins related to amyloid deposited brain of Tg2576 mice. Proteomics
4: 3359 –3368, 2004.
286. Shringarpure R, Grune T, Sitte N, Davies KJA.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer’s disease. Cell Mol Life Sci 57:
1802–1809, 2000.
287. Siegel SJ, Bieschke J, Powers ET, Kelly JW. The
oxidative stress metabolite 4-hydroxynonenal
promotes Alzheimer protofibril formation. Biochemistry 46: 1503–1510, 2007.
273. Sayre LM, Perry G, Harris PLR, Liu YH, Schubert
KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition
metals. J Neurochem 74: 270 –279, 2000.
288. Simons M, Keller P, De Strooper B, Beyreuther
K, Dotti CG, Simons K. Cholesterol depletion
inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:
6460 – 6464, 1998.
274. Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenal-derived
advanced lipid peroxidation end products are
increased in Alzheimer’s disease. J Neurochem
68: 2092–2097, 1997.
289. Sjogren M, Blennow K. The link between cholesterol and Alzheimer’s disease. World J Biol Psych
6: 85–97, 2005.
275. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava
S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson
PWF, Wolf PA. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia
and Alzheimer disease: the Framingham heart
study. Arch Neurol 63: 1545–1550, 2006.
276. Schauerte JA, Wong PT, Wisser KC, Ding H, Steel
DG, Gafni A. Simultaneous single molecule fluorescence and conductivity studies reveal distinct
classes of A␤ species on lipid bilayers. Biochemistry 49: 3031–3039, 2010.
277. Schippling S, Kontush A, Arlt S, Buhmann C,
Sturenburg HJ, Mann U, Muller-Thomsen T,
Beisiegel U. Increased lipoprotein oxidation in
Alzheimer’s disease. Free Radic Biol Med 28:
351–360, 2000.
278. Schmechel DE, Saunders AM, Strittmatter WJ,
Crain BJ, Huletter CM, Joo SH, Pericakvance MA,
Goldgaber D, Roses AD. Increased amyloid betapeptide deposition in cerebral-cortex as a consequence of apolipoprotein-E genotype in lateonset Alzheimer-disease. Proc Natl Acad Sci USA
90: 9649 –9653, 1993.
279. Schmitz C, Rutten BPF, Pielen A, Schafer S,
Wirths O, Tremp G, Czech C, Blanchard V,
Multhaup G, Rezaie P, Korr H, Steinbusch HWM,
Pradier L, Bayer TA. Hippocampal neuron loss
exceeds amyloid plaque load in a transgenic
mouse model of Alzheimer’s disease. Am J
Pathol 164: 1495–1502, 2004.
280. Schneeweis LA, Koppaka V, Lund-Katz S, Phillips
MC, Axelsen PH. Structural analysis of lipoprotein E particles. Biochemistry 44: 12525–12534,
2005.
281. Sengupta P, Garai K, Sahoo B, Shi Y, Callaway
DJE, Maiti S. The amyloid beta peptide [A beta(140)] is thermodynamically soluble at physiological
concentrations. Biochemistry 42: 10506 –10513,
2003.
282. Shankar GM, Li SM, Mehta TH, Garcia-Munoz A,
Shepardson NE, Smith I, Brett FM, Farrell MA,
Rowan MJ, Lemere CA, Regan CM, Walsh DM,
Sabatini BL, Selkoe DJ. Amyloid-beta protein
dimers isolated directly from Alzheimer’s brains
impair synaptic plasticity and memory. Nat Med
14: 837– 842, 2008.
283. Shao H, Jao S, Ma K, Zagorski MG. Solution
structures of micelle-bound amyloid beta-(1-40)
and beta-(1-42) peptides of Alzheimer’s disease.
J Mol Biol 285: 755–773, 1999.
284. Shearer J, Szalai VA. The Amyloid-␤ peptide of
Alzheimer’s disease binds Cu⫹ in a linear Bis-His
coordination environment: insight into a possible
neuroprotective mechanism for the amyloid-␤
peptide. J Am Chem Soc 130: 17826 –17835,
2008.
290. Smith DP, Ciccotosto GD, Tew DJ, Fodero-Tavoletti MT, Johanssen T, Masters CL, Barnham KJ,
Cappai R. Concentration dependent Cu2⫹ induced aggregation and dityrosine formation of
the Alzheimer’s disease amyloid-␤ peptide. Biochemistry 46: 2881–2891, 2007.
291. Smith DP, Smith DG, Curtain CC, Boas JF, Pilbrow JR, Ciccotosto GD, Lau TL, Tew DJ, Perez
K, Wade JD, Bush AI, Drew SC, Separovic F,
Masters CL, Cappai R, Barnham KJ. Copper mediated amyloid-beta toxicity is associated with an
intermolecular histidine bridge. J Biol Chem 281:
15145–15154, 2006.
292. Smith MA, Casadesus G, Joseph JA, Perry G.
Amyloid-beta and tau serve antioxidant functions
in the aging and Alzheimer brain. Free Radic Biol
Med 33: 1194 –1199, 2002.
293. Smith MA, Harris PLR, Sayre LM, Beckman JS,
Perry G. Widespread peroxynitrite-mediated
damage in Alzheimer’s disease. J Neurosci 17:
2653–2657, 1997.
294. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris
PLR, Siedlak SL, Tabaton M, Perry G. Amyloidbeta deposition in Alzheimer transgenic mice is
associated with oxidative stress. J Neurochem
70: 2212–2215, 1998.
295. Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N. Oxidative damage in
Alzheimer’s. Nature 382: 120 –121, 1996.
296. Smith MA, Taneda S, Richey PL, Miyata S, Yan
SD, Stern D, Sayre LM, Monnier VM, Perry G.
Advanced Maillard reaction end-products are associated with Alzheimer-disease pathology. Proc
Natl Acad Sci USA 91: 5710 –5714, 1994.
297. Sokolov Y, Kozak JA, Kayed R, Chanturiya A,
Glabe C, Hall JE. Soluble amyloid oligomers increase bilayer conductance by altering dielectric
structure. J Gen Physiol 128: 637– 647, 2006.
298. Song WL, Lawson JA, Reilly D, Rokach J, Chang
CT, Giasson B, FitzGerald GA. Neurofurans,
novel indices of oxidant stress derived from docosahexaenoic acid. J Biol Chem 283: 6 –16,
2008.
299. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM,
Ingelsson M, Hyman B, Burton MA, Goldstein LE,
Duong S, Tanzi RE, Moir RD. The Alzheimer’s
disease-associated amyloid ␤-protein is an antimicrobial peptide. PLoS ONE 5: e9505, 2010.
300. Sparks DL, Scheff SW, Hunsaker JC, Liu HC,
Landers T, Gross DR. Induction of Alzheimer-like
beta-amyloid immunoreactivity in the brains of
rabbits with dietary-cholesterol. Exp Neurol 126:
88 –94, 1994.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
67
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
259. Quist A, Doudevski L, Lin H, Azimova R, Ng D,
Frangione B, Kagan B, Ghiso J, Lal R. Amyloid ion
channels: a common structural link for proteinmisfolding disease. Proc Natl Acad Sci USA 102:
10427–10432, 2005.
271. Sanan DA, Weisgraber KH, Russell SJ, Mahley
RW, Huang D, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD, Strittmatter
WJ. Apolipoprotein-E associates with beta-amyloid peptide of Alzheimers-disease to form novel
monofibrils: isoform Apoe4 associates more Efficiently than Apoe3. J Clin Invest 94: 860 – 869,
1994.
REVIEWS
301. Stewart CR, Wilson LM, Zhang Q, Pham CLL,
Waddington LJ, Staples MK, Stapleton D, Kelly
JW, Howlett GJ. Oxidized cholesterol metabolites found in human atherosclerotic lesions promote apolipoprotein C-II amyloid fibril formation.
Biochemistry 46: 5552–5561, 2007.
302. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah
E, Williams DS, Goldstein LSB. Axonopathy and
transport deficits early in the pathogenesis of
Alzheimer’s disease. Science 307: 1282–1288,
2005.
303. Stratman NC, Castle CK, Taylor BM, Epps DE,
Melchior GW, Carter DB. Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloidbeta peptide. Chem Phys Lipids 137: 52– 61,
2005.
305. Streltsov VA. X-ray absorption and diffraction
studies of the metal binding sites in amyloid beta-peptide. Eur Biophys J 37: 257–263, 2008.
306. Streltsov VA, Titmuss SJ, Epa VC, Barnham KJ,
Masters CL, Varghese JN. The structure of the
amyloid-beta peptide high-affinity copper II
binding site in Alzheimer disease. Biophys J 95:
3447–3456, 2008.
307. Strittmatter WJ, Weisgraber KH, Huang DY,
Dong LM, Salvesen GS, Pericakvance M, Schmechel D, Saunders AM, Goldgaber D, Roses
AD. Binding of human apolipoprotein-E to synthetic amyloid-beta peptide: isoform-specific effects and implications for late-onset Alzheimerdisease. Proc Natl Acad Sci USA 90: 8098 – 8102,
1993.
308. Subasinghe S, Unabia S, Barrow CJ, Mok SS,
Aguilar MI, Small DH. Cholesterol is necessary
both for the toxic effect of A beta peptides on
vascular smooth muscle cells and for A beta binding to vascular smooth muscle cell membranes. J
Neurochem 84: 471– 479, 2003.
309. Sultana R, Butterfield DA. Oxidatively modified
GST and MRP1 in Alzheimer’s disease brain: implications for accumulation of reactive lipid peroxidation products. Neurochem Res 29: 2215–
2220, 2004.
310. Surewicz WK, Mantsch HH. The conformation of
dynorphin A-(1-13) in aqueous solution as studied by Fourier transform infrared spectroscopy. J
Mol Struct 214, 143–147, 1989.
311. Svennerholm L, Gottfries CG. Membrane-lipids,
selectively diminished in Alzheimer brains, suggest
synapse loss as a primary event in early-onset form
(type-I) and demyelination in late-onset form (typeII). J Neurochem 62: 1039 –1047, 1994.
312. Tamaoka A, Miyatake F, Matsuno S, Ishii K, Nagase S, Sahara N, Ono S, Mori H, Wakabayashi K,
Tsuji S, Takahashi H, Shoji S. Apolipoprotein E
allele-dependent antioxidant activity in brains
with Alzheimer’s disease. Neurol 54: 2319 –2321,
2000.
313. Terzi E, Holzemann G, Seelig J. Alzheimer betaamyloid peptide 25-35: electrostatic interactions
with phospholipid membranes. Biochemistry 33:
7434 –7441, 1994.
314. Terzi E, Holzemann G, Seelig J. Self-association
of beta-amyloid peptide (1-40) in solution and
binding to lipid membranes. J Mol Biol 252: 633–
642, 1995.
315. Terzi E, Holzemann G, Seelig J. Interaction of Alzheimer beta-amyloid peptide(1-40) with lipid
membranes. Biochemistry 36: 14845–14852,
1997.
68
317. Tien M, Berlett BS, Levine RL, Chock PB, Stadtman ER. Peroxynitrite-mediated modification of
proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation,
tyrosine nitration, and methionine oxidation.
Proc Natl Acad Sci USA 96: 7809 –7814, 1999.
318. Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R,
Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H. A mouse
model of amyloid ␤ oligomers: their contribution
to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J
Neurosci 30: 4845– 4856, 2010.
319. Torp R, Head E, Milgram NW, Hahn F, Ottersen
OP, Cotman CW. Ultrastructural evidence of
fibrillar beta-amyloid associated with neuronal
membranes in behaviorally characterized aged
dog brains. Neuroscience 96: 495–506, 2000.
320. Townsend M, Shankar GM, Mehta T, Walsh DM,
Selkoe DJ. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol 572:
477– 492, 2006.
321. Treiber C, Quadir MA, Voigt P, Radowski M, Xu
SJ, Munter LM, Bayer TA, Schaefer M, Haag R,
Multhaup G. Cellular copper import by nanocarrier systems, intracellular availability, and effects
on amyloid beta peptide secretion. Biochemistry
48: 4273– 4284, 2009.
322. Trojanowski JQ, Lee VM. The role of tau in Alzheimer’s disease. Med Clin North Am 86: 615–
627, 2002.
323. Tully AM, Roche HM, Doyle R, Fallon C, Bruce I,
Lawlor B, Coakley D, Gibney MJ. Low serum
cholesteryl ester-docosahexaenoic acid levels in
Alzheimer’s disease: a case-control study. Br J
Nutr 89: 483– 489, 2003.
324. Uchida K. Current status of acrolein as a lipid
peroxidation product. Trends Cardiovasc Med 9:
109 –113, 1999.
325. Uchida K. 4-Hydroxy-2-nonenal: a product and
mediator of oxidative stress. Prog Lipid Res 42:
318 –343, 2003.
326. Uchida K, Kanematsu M, Morimitsu Y, Osawa T,
Noguchi N, Niki E. Acrolein is a product of lipid
peroxidation reaction: formation of free acrolein
and its conjugate with lysine residues in oxidized
low density lipoproteins. J Biol Chem 273:
16058 –16066, 1998.
327. Uchida K, Kanematsu M, Sakai K, Matsuda T,
Hattori N, Mizuno Y, Suzuki D, Miyata T, Noguchi
N, Niki E, Osawa T. Protein-bound acrolein: potential markers for oxidative stress. Proc Natl
Acad Sci USA 95: 4882– 4887, 1998.
328. Uchida K, Stadtman ER. Modification of histidineresidues in proteins by reaction with 4-hydroxynonenal. Proc Natl Acad Sci USA 89: 4544 –
4548, 1992.
329. Usui K, Hulleman JD, Paulsson JF, Siegel SJ, Powers ET, Kelly JW. Site-specific modification of
Alzheimer’s peptides by cholesterol oxidation
products enhances aggregation energetics and
neurotoxicity. Proc Natl Acad Sci USA 106:
18563–18568, 2009.
330. Van Nostrand WE, Melchor JP, Ruffini L. Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular
smooth muscle cells. J Neurochem 70: 216 –223,
1998.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
331. Varadarajan S, Yatin S, Aksenova M, Butterfield
DA. Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130: 184 –208, 2000.
332. Varadarajan S, Yatin S, Butterfield DA. Alzheimer’s amyloid beta peptide (1-42) fibrils are not
always neurotoxic. Alzheimers Rep 3: 71–76,
2000.
333. Wahrle SE, Jiang H, Parsadanian M, Hartman RE,
Bales KR, Paul SM, Holtzman DM. Deletion of
Abca1 increases A beta deposition in the PDAPP
transgenic mouse model of Alzheimer disease. J
Biol Chem 280: 43236 – 43242, 2005.
334. Wakabayashi M, Matsuzaki K. Formation of amyloids by a beta-(1-42) on NGF-differentiated
PC12 cells: roles of gangliosides and cholesterol.
J Mol Biol 371: 924 –933, 2007.
335. Wakabayashi M, Okada T, Kozutsumi Y, Matsuzaki K. GM1 ganglioside-mediated accumulation
of amyloid beta-protein on cell membranes.
Biochem Biophys Res Commun 328: 1019 –1023,
2005.
336. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK,
Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein
potently inhibit hippocampal long-term potentiation in vivo. Nature 416: 535–539, 2002.
337. Walsh DM, Lomakin A, Benedek GB, Condron
MM, Teplow DB. Amyloid beta-protein fibrillogenesis: detection of a protofibrillar intermediate. J Biol Chem 272: 22364 –22372, 1997.
338. Wang SSS, Rymer DL, Good TA. Reduction in
cholesterol and sialic acid content protects cells
from the toxic effects of beta-amyloid peptides.
J Biol Chem 276: 42027– 42034, 2001.
339. Waschuk SA, Elton EA, Darabie AA, Fraser PE,
McLaurin J. Cellular membrane composition defines Abeta-lipid interactions. J Biol Chem 276:
33561–33568, 2001.
340. Weisgraber KH, Shinto LH. Identification of the
disulfide-linked homodimer of apolipoprotein E3
in plasma: impact on receptor-binding activity. J
Biol Chem 266: 12029 –12034, 1991.
341. Widenbrant MJO, Rajadas J, Sutardja C, Fuller
GG. Lipid-induced ␤-amyloid peptide assemblage fragmentation. Biophys J 91: 4071– 4080,
2006.
342. Williams TI, Lynn BC, Markesbery WR, Lovell MA.
Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in
the brain in mild cognitive impairment and early
Alzheimer’s disease. Neurobiol Aging 27: 1094 –
1099, 2006.
343. Wisniewski T, Castano EM, Golabek A, Vogel T,
Frangione B. Acceleration of Alzheimers fibril formation by apolipoprotein-E in-vitro. Am J Pathol
145: 1030 –1035, 1994.
344. Wong PT, Schauerte JA, Wisser KC, Ding H, Lee
EL, Steel DG, Gafni A. Amyloid-beta membrane
binding and permeabilization are distinct processes influenced separately by membrane
charge and fluidity. J Mol Biol 386: 81–96, 2009.
345. Wu Y, Luo Y. Transgenic C. elegans as a model in
Alzheimer’s research. Curr Alzheimer Res 2: 37–
47, 2005.
346. Yamaguchi H, Maat-Schieman MLC, van Duinen
SG, Prins FA, Neeskens P, Natte R, Roos RAC.
Amyloid beta protein (A beta) starts to deposit as
plasma membrane-bound form in diffuse plaques
of brains from hereditary cerebral hemorrhage
with amyloidosis-Dutch type, Alzheimer disease
and nondemented aged subjects. J Neuropath
Exp Neurol 59: 723–732, 2000.
347. Yamazaki T, Chang TY, Haass C, Ihara Y. Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-Pick type C
cells. J Biol Chem 276: 4454 – 4460, 2001.
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
304. Strausak D, Mercer JFB, Dieter HH, Stremmel W,
Multhaup G. Copper in disorders with neurological symptoms: Alzheimer’s, Menkes, and Wilson
diseases. Brain Res Bull 55: 175–185, 2001.
316. Tickler AK, Smith DG, Ciccotosto GD, Tew DJ,
Curtain CC, Carrington D, Masters CL, Bush AI,
Cherny RA, Cappai R, Wade JD, Barnham KJ.
Methylation of the imidazole side chains of the
Alzheimer disease amyloid-␤ peptide results in
abolition of superoxide dismutase-like structures
and inhibition of neurotoxicity. J Biol Chem 280:
13355–13363, 2005.
REVIEWS
348. Yanagisawa K, Odaka A, Suzuki N, Ihara Y. GM1
ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s
disease. Nat Med 1: 1062–1066, 1995.
349. Yang DS, Smith JD, Zhou ZM, Gandy SE, Martins
RN. Characterization of the binding of amyloidbeta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to
isoforms from human plasma. J Neurochem 68:
721–725, 1997.
350. Yao JK, Wengenack TM, Curran GL, Poduslo JF.
Reduced membrane lipids in the cortex of Alzheimer’s disease transgenic mice. Neurochem
Res 34: 102–108, 2009.
351. Yao ZX, Drieu K, Szweda LI, Papadopoulos V.
Free radicals and lipid peroxidation do not mediate beta-amyloid-induced neuronal cell death.
Brain Res 847: 203–210, 1999.
353. Yip CM, McLaurin J. Amyloid-beta peptide assembly: a critical step in fibrillogenesis and membrane disruption. Biophys J 80: 1359 –1371,
2001.
360. Zhang QH, Powers ET, Nieva J, Huff ME, Dendle
MA, Bieschke J, Glabe CG, Eschenmoser A,
Wentworth P, Lerner RA, Kelly JW. Metaboliteinitiated protein misfolding may trigger Alzheimer’s disease. Proc Natl Acad Sci USA 101:
4752– 4757, 2004.
356. Yoshimoto N, Tasaki M, Shimanouchi T, Umakoshi H, Kuboi R. Oxidation of cholesterol catalyzed
by amyloid beta-peptide (A beta)-Cu complex on
lipid membrane. J Biosci Bioeng 100: 455– 459,
2005.
361. Zhou S, Zhou H, Walian PJ, Jap BK. Regulation of
␥-secretase activity in Alzheimer’s disease. Biochemistry 46: 2553–2563, 2007.
357. Zagol-Ikapitte I, Masterson TS, Amarnath V,
Montine TJ, Andreasson KI, Boutaud O, Oates
JA. Prostaglandin H-2-derived adducts of proteins correlate with Alzheimer’s disease severity.
J Neurochem 94: 1140 –1145, 2005.
358. Zaman Z, Roche S, Fielden P, Frost PG, Niriella
DC, Cayley AC. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer’s
disease. Age Ageing 21: 91–94, 1992.
359. Zerbinatti CV, Wahrle SE, Kim H, Cam JA, Bales
K, Paul SM, Holtzman DM, Bu GJ. Apolipoprotein
E and low density lipoprotein receptor-related
protein facilitate intraneuronal A beta 42 accumulation in amyloid model mice. J Biol Chem
281: 36180 –36186, 2006.
362. Zommara M, Tachibana N, Mitsui K, Nakatani N,
Sakono M, Ikeda I, Imaizumi K. Inhibitory effect
of ethanolamine plasmalogen on iron-dependent
and copper-dependent lipid-peroxidation. Free
Radic Biol Med 18: 599 – 602, 1995.
363. Zou K, Gong JS, Yanagisawa K, Michikawa M. A
novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against
metal-induced oxidative damage. J Neurosci 22:
4833– 4841, 2002.
364. Zubenko GS. Hippocampal membrane-alteration
in Alzheimers-disease. Brain Res 385: 115–121,
1986.
354. Yoshiike Y, Kayed R, Milton SC, Takashima A,
Glabe CG. Pore-forming proteins share structural
and functional homology with amyloid oligomers.
Neuromol Med 9: 270 –275, 2007.
PHYSIOLOGY • Volume 26 • February 2011 • www.physiologyonline.org
69
Downloaded from http://physiologyonline.physiology.org/ by 10.220.32.247 on June 15, 2017
352. Yip CM, Darabie AA, McLaurin J. A beta 42peptide assembly on lipid bilayers. J Mol Biol
318: 97–107, 2002.
355. Yoshiike Y, Tanemura K, Murayama O, Akagi T,
Murayama M, Sato S, Sun XY, Tanaka N,
Takashima A. New insights on how metals disrupt amyloid beta-aggregation and their effects
on amyloid-beta cytotoxicity. J Biol Chem 276:
32293–32299, 2001.