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Neuropathological changes in mouse models of cardiovascular diseases
Bink, D.I.
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Bink, D. I. (2016). Neuropathological changes in mouse models of cardiovascular diseases
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Download date: 17 Jun 2017
2|
Mouse models to study the effect of cardiovascular
risk factors on brain structure and cognition
Diewertje I. Bink, Katja Ritz, Eleonora Aronica, Louise van der Weerd,
Mat J.A.P. Daemen
Adapted from: Journal of Cerebral Blood Flow & Metabolism. 2013
Nov;33(11):1666-84.
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CHAPTER 2
Abstract
Recent clinical data indicates that hemodynamic changes caused by cardiovascular
diseases like atherosclerosis, heart failure and hypertension affect cognition. Yet the
underlying mechanisms of the resulting vascular cognitive impairment (VCI) are
poorly understood. One reason for the lack of mechanistic insights in VCI is that
research in dementia primarily focused on Alzheimer’s disease models. To fill in this
gap we critically reviewed the published data and various models of VCI. Typical
findings in VCI include reduced cerebral perfusion, blood-brain barrier alterations,
white matter lesions and cognitive deficits, which have also been reported in different
cardiovascular mouse models. However, the tests performed are incomplete and
differ between models, hampering a direct comparison between models and studies.
Nevertheless, from the currently available data we conclude that a few existing surgical
animal models show the key features of vascular cognitive decline, with the bilateral
common carotid artery stenosis hypoperfusion mouse model as the most promising
model. The transverse aortic constriction and myocardial infarction models may be
good alternatives, but these models are as yet less characterized regarding possible
cerebral changes. Mixed models could be used to study the combined effects of
different cardiovascular diseases on the deterioration of cognition during aging.
28
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Effect of CVD on brain structure and cognition
Introduction
Epidemiology of vascular cognitive impairment (VCI)
Dementia has an overall prevalence of 5-7% in ≥60-year-old people.1 After Alzheimer’s
disease (AD), vascular dementia (VaD) is the second most common form of
dementia.2 It is the most severe form of vascular cognitive impairment (VCI), which
is the collection of all cognitive changes from mild cognitive impairment to dementia,
caused by any cardiovascular factor.3 As the prevalence of both cardiovascular diseases
(CVD) and dementia increases with age, the rising percentage of aged people in the
population will lead to a high number of cardiovascular and dementia patients in
the near future. For the year 2010, 35.6 million dementia cases were estimated and
this number will increase to approximately 65.7 million in 2030 and 115.4 million
in 2050.1 Moreover, considering that dementia is estimated as the most burdensome
neuropsychiatric disorder in elderly,4 this will lead to an enormous increase in costs
and need of caregivers in the upcoming years.
2
CVD and cognition: evidence in humans
CVD such as heart failure (HF), atherosclerosis and hypertension are associated with
an increased risk of cognitive impairment and dementia.5-11 One of the mechanisms
by which CVD can affect cognition is by influencing the blood flow to, and in,
the brain. The effect of altered cerebral hemodynamics on cognitive function have
been extensively reviewed.12-13 CVD may reduce cerebral blood flow (CBF), which
is associated with cognitive decline.14-16 In addition to global perfusion changes,
vascular autoregulation may be compromised, causing an enhanced vulnerability
to hypoperfusion, as was shown in elderly people with hypertension.17 Intriguingly,
improvement of heart function or blood pressure has positive effects on cognitive
functioning. Clinical studies showed for example that cardiac transplantation led
to improved cognitive abilities.18 Similar improvements in cognitive function were
obtained using cardiac resynchronization therapy or ACE inhibitors in patients with
heart failure.19-20 Carotid artery stenting in patients with carotid stenosis and cognitive
impairment also significantly improves cognition.21
Apart from these effects on brain function, also structural brain abnormalities are
associated with CVD, including white matter lesions, BBB alterations, microinfarcts,
brain atrophy and cerebral inflammation.3, 7, 22-23 However, the causal links between these
associations are largely unknown. Cerebral hypoperfusion may be an important link
between CVD and cognitive decline,12 but this hypothesis is not generally accepted.
29
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Although multiple association studies have suggested a link between cerebral blood flow
and VCI, the evidence is still incomplete as data from prospective studies is still lacking.
Therefore, more basic research is needed to understand the mechanisms underlying
these clinical observations.
Animal research
In the dementia field, animal research has focused almost exclusively on mouse models
of Alzheimer’s disease, while only limited research has been done on other forms of
dementia. As cerebral hypoperfusion models mostly involve surgical interventions,
many studies have been performed in rats. In a few studies monkeys are used, because
their brains physiologically more resemble the human brain. Nevertheless, mouse
models are preferred to study the relation of CV dysfunction on cerebral perfusion
and cognition, because of the plethora of genetic models available. These models allow
investigation of the interactions between different risk factors and comorbidities, and
dissection of the molecular mechanisms involved.
Therefore, this literature review focuses on the published cerebral data in mouse models
of cardiovascular diseases, selects the models suited best to study the mechanisms of
VCI and pinpoints gaps in the literature. It includes mouse models for atherosclerosis,
heart failure, and cerebral hypoperfusion and briefly addresses hypertension and
CADASIL models. Histological brain changes, cerebral vascular reactivity and
functional cerebral changes will be discussed.
Search strategy
Studies of potentially interesting mouse models were identified from Pubmed with
the search terms: ‘Mouse’ AND ‘Brain’ OR ‘Cerebral’ AND ‘Atherosclerosis’ OR
‘Hypertension’ OR ‘Heart failure’ OR ‘Perfusion’ OR ‘CADASIL’. Furthermore search
terms such as ‘Cognition’, ‘Memory’, ‘MRI’, ‘CBF’ in combination with ‘Mouse’ and
cross-references were used to increase the amount of potentially interesting models
and papers. Exclusion criteria were: human data; stroke data; non-cerebral data; distal
MCA occlusion models; articles that did not contain a clear comparison with an
appropriate control group.
Study quality according to CAMARADES criteria
To judge the study quality and reliability of the papers we scored all included
papers according to the CAMARADES criteria. We used the criteria as described
30
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Effect of CVD on brain structure and cognition
Table 1. The adjusted CAMARADES checklist with definitions as used for this review
2
by Sena et al., with the with the exclusion of two criteria that is “allocation
concealment” and ”use of animals with hypertension and diabetes”.24 ‘Allocation
concealment’ was excluded since we did not include data with treatment effects
because this was beyond the scope of this review. The criterion ‘Use of animals with
hypertension and diabetes’ was excluded because this criterion is specific for stroke
models. Definitions of the other criteria used in our review are provided in table 1.
The amount of studies that report the study quality criteria is shown in table 2.
Publications perform poorly on (reporting) sample-size calculation, blinded assessment
of outcome, randomization and statement conflict of interest. However, there are a few
limitations with estimating study quality according to these criteria.
A statement of conflict of interest indicated by the authors may be provided by the
authors to the journal but may not have been included in the published manuscript,
underestimating the study quality for these manuscripts.25
Furthermore, sample-size calculations are at least in the Netherlands a mandatory
part for approval of the experiment by the ethical committee, which means these
calculations have been performed for a number of these studies, though not
mentioned in the manuscript. Samaranayake also showed that a priori sample-size
calculations are underreported.25
The score given to the criterion ’avoidance of anesthesia with intrinsic neuroprotective
properties’ may not be relevant for our models. The value was based on the scores
given to stroke papers in systematic reviews by Macleod.26-28 However, the score of
this criterion was based on the reduction of brain infarct size by ketamine and the
overestimation of treatment effect size after ketamine anesthesia in animals models of
31
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Bink DB Proefschrift 160218.indd 32
The colours in the table indicate the proportion of studies meeting the criterion: underlined <25%; bold, 25% to 50%; italics, 50% to 75%; standard,
>75%. Publications perform poorly on (reporting) sample-size calculation, blinded assessment of outcome, randomization and statement conflict of
interest.
Table 2. Quality characteristics of the adjusted CAMARADES
CHAPTER 2
32
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Effect of CVD on brain structure and cognition
stroke. It is not known whether ketamine will have the same effect in animal models of
VCI. For the VCI models, and especially the functional and perfusion measurements,
the cardiovascular properties of the anesthetics may be of bigger importance for
estimating outcome and treatment effect. For example, inhalation anesthetics
like isoflurane lead to vasodilation and hypotension, thus influencing the cerebral
perfusion and autoregulation measurements.29 This criterion may therefore still need
an adjustment for VCI models in the future and may have led to inaccurate scores for
study quality in the current analysis.
2
The average quality per study was 51%. Five of the 93 publications scored below 25%
and were excluded from this review (supplemental table 1).
Atherosclerosis models
The pathology of atherosclerosis generally starts with the accumulation of oxidized
LDL particles in the intima of an artery, leading to an immune response, and
formation and accumulation of foam cells.30 Atherosclerosis causes narrowing of
vessels, thereby limiting the blood flow and reducing the capacity of the vessels to
dilate. The end stage of atherosclerosis commonly leads to ischemia and infarction in
the heart (myocardial infarction, MI) or brain (cerebral infarction).
Mice do normally not develop atherosclerosis. Most of the atherosclerotic mouse
models are therefore based on alterations in the ApoE, ApoB and LDLr genes. Apart
from these genetic modifications, there is a difference in vulnerability between strains
for developing atherosclerosis, with C57Bl/6 mice being the most susceptible inbred
strain.31 The C57Bl/6 strain is therefore used as background for the atherogenic
models and as wild-type (WT) control. As in humans, the degree of atherosclerosis in
these mouse models depends on diet, with high-fat and high-cholesterol diets leading
to a faster disease progression.
Table 3 shows an overview of all cerebral changes found in atherogenic mouse models.
Data of atherogenic models that are combined with other models, surgeries or
treatments in respect to the baseline model are not included in the tables.
ApoE knockout mice
The ApoE-/- mouse model is the classical model of atherosclerosis. These mice start
to develop severe hypercholesterolemia and atherosclerotic lesions in the aorta and
33
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Table 3. Structural and functional brain changes in atherosclerotic mouse models
CHAPTER 2
34
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Effect of CVD on brain structure and cognition
Table 3. Continued
2
35
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AD: Alzheimer’s disease; BBB: blood-brain barrier; CBF: Cerebral blood flow; ChAT: Choline acetyltransferase; DG: Dentate gyrus; EM: electron
microscopy; FMD: flow-mediated dilation; GSH: Glutathione; HB: Hole board; HCD: High-cholesterol diet; HFD: High-fat diet; LCD: Low cholesterol
diet; LTP: Long-term potentiation; NSC: Neural stem cells; MWM: Morris water maze; OF: Open field; PPI: Prepulse inhibition; SGZ: Subgranular
zone; WD: Western diet. Differences compared to wild-type mice with the same diet unless stated otherwise; n = number of animals per group
Table 3. Continued
CHAPTER 2
36
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Effect of CVD on brain structure and cognition
pulmonary, coronary and carotid arteries at the age of 8 or 10 weeks depending on
the type of diet.32-33 The cardiovascular features of this model have been researched
extensively, yet only a few studies investigated cerebral perfusion in ApoE-/- mice.
2
Cerebral perfusion
In young mice (6-8 weeks), the cerebral blood volume of the total brain and the CBF
were equal in ApoE-/- mice and controls.34-35 In a different study regional CBF was
already reduced at 2 weeks of age and decreased progressively.36
Inflammatory response
ApoE-/- mice fed a high-fat/high-cholate diet (Paigen) for 8 weeks showed significantly
increased intracerebral expression of the vascular adhesion molecules ICAM and
VCAM, which are markers for endothelial activation.37 In the brain, VCAM was
mainly localized on the large and medium-sized vessels in the cerebral cortex, striatum,
thalamus and hippocampus. Lipid deposits were found in the vessel walls, and were
accompanied by leukocyte recruitment and microglial activation, the brain’s main
active immune defense. This immune response was found partly in the same brain
regions that show endothelial activation: the cerebral cortex, striatum, hypothalamus,
periventricular areas and meninges.37 Chow-fed ApoE-/- mice, and chow or Paigen-fed
WT mice did not show microglial activation.
Blood-brain barrier
The BBB is probably the most studied part of the brain in ApoE-/- mice. Compared
to WT mice, more spontaneous leakage is seen from 2 weeks of age, which is worse
after a Western diet.34, 36, 38-41 Recently, a mechanism has been proposed in which the
increased BBB leakage is postulated to be due to a direct loss of the inhibitory effect of
ApoE on the activation of the pro-inflammatory cyclophilin A (CypA) – nuclear factor
κB (NF-κB) – matrix metalloproteinase-9 (MMP-9) pathway.36 Deletion of the CypA
gene Ppia in ApoE-/- mice normalized the CBF reductions, BBB integrity and levels of
NK-κB and MMP-9. In this mouse model, Bell et al. showed that the degeneration of
the microvessels and reductions in microvascular length was correlated with the degree
of BBB breakdown and CBF reduction and preceded neuronal and synaptic changes.
Synaptic and dendritic organization
Deficiency of ApoE leads to several cellular and molecular changes in the hippocampus,
one of the most important regions for (spatial) memory formation. ApoE-/- mice
37
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exhibited decreased neurogenesis in the subgranular zone of the dentate gyrus, and
an increase of astrogenesis.42 These changes may be explained by the direct effects of
ApoE on neural progenitor cells.43 However, the number and proliferation of neural
stem/progenitor cells and the number of GABAergic interneurons were not affected.42
Intriguingly, synaptic plasticity in the hippocampus was affected in 4 to 10-month-old
mice, but not in 18-month-old ApoE-/- mice.44-45
The synaptic and dendritic organization was disrupted in ApoE-deficient mice in both
the limbic system and neocortex.46 As ApoE-/- mice age, presynaptic terminals and
neuronal dendrites were lost faster in the hippocampus and cortex compared to WT
mice, and hippocampal neurofilament-positive axons were also more disrupted.47
Cognitive and behavioral changes
ApoE-deficient mice have spatial memory impairment compared to WT during the
Morris water maze (MWM) test.48-52 Surprisingly, under stress learning and memory
of ApoE-/- mice improves, reducing their latencies and switching to a goal directed
search strategy, performing similar or even better than control mice.48-49 This finding
is attributed to ApoE genotype related differences in the regulation of corticosterone
levels and expression of cell adhesion molecules.49
Relation to Alzheimer’s disease
ApoE-deficient mice show several hallmarks of AD, like a reduced clearance of Aβ 53
and the presence of hyperphosphorylated tau.54 However, cross breeding of ApoE-/mice with different AD mouse models (5XFAD, PDAPP) resulted in a decrease in
the amount of amyloid plaques without any effect on the inflammatory response.55,56
Neurodegeneration has not been studied in these models.
In summary, ApoE-/- mice exhibit increased inflammation, increased BBB permeability,
microvessel degeneration, reduction of neurogenesis and synapses and cognitive
impairment (see table 3). The cerebral changes are mostly increased or accelerated
when the animals are fed a high-fat diet. There are no studies investigating CBF in
combination with cellular or molecular changes in normal ApoE-/- mice. Therefore, it
remains unclear whether these changes are the result of atherosclerosis-induced CBF
reduction or the direct effects of the lack of ApoE.
hApoB
ApoB, which is part of lipoproteins, LDL and chylomicrons, plays an important role
38
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Effect of CVD on brain structure and cognition
in cholesterol transport. Human ApoB transgenic mice have shown extensive aortic
atherosclerotic lesions and a reduction of approximately 25% in aortic blood flow after
18 weeks on a high-fat diet.57-58 These effects were not present when fed a chow diet,
possibly due to the fact that although triglyceride levels were elevated with both diets,
cholesterol was only elevated when the mice were fed a high-fat diet.58-59
Nevertheless, also on a chow diet, ApoB transgenic animals showed an increase in
apoptotic signaling proteins and cytoskeletal proteins in the brain at the age of 6-7
months.59 In addition, extensive neuronal death and amyloid plaques were detected in
the hippocampus, cerebral cortex and hypothalamus.
With MRI, an enlargement of the cerebral ventricles has been found in these mice,
irrespective of diet, which was proportional to the elevated human ApoB100 levels.59
As yet, there is no data available on cerebral perfusion, BBB integrity, inflammation or
cognition for these mice.
2
LDLr knockout mice
The LDLr-/- mouse model is a commonly used model for atherosclerosis. Mutations
in the LDLr gene cause familial hypercholesterolemia in humans.60 On a normal
diet the LDLr-/- mice slowly develop atherosclerosis over time; as for the other
models this process is accelerated with a high-fat diet. These mice have increased
plasma cholesterol levels with both standard and fat diets, but the cholesterol level
in cholesterol-enriched-fed mice is 3-fold higher than on a standard diet.61 However,
despite the elevated plasma cholesterol, the brain cholesterol does not differ between
LDLr-/- mice and WT mice, irrespective of the diet.62-64
CBF, blood-brain barrier and brain vasculature
The effect of LDLr-/- on cerebral blood flow is not yet known. In contrast to ApoE-/mice, young LDLr knockout mice (9 weeks old) did not show BBB deficits.34 At
the age of 6-12 months LDLr-/- mice showed more pathological changes in the
CNS microvessels than WT when fed with a normal chow diet, including an overall
increased diameter, a mixture of thin and irregular as well as enlarged microvessels,
very thin “string-like” vessels and vessels with a kinked or twisted morphology.65 These
changes were more apparent in older mice.
Inflammatory response and synaptic and dendritic organization
Hippocampal levels of cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)1β, and IL-6) and proinflammatory enzymes (iNOS and COX2) were increased in
39
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LDLr-/- mice compared to WT mice on a chow diet at the age of 6 months.66 The
levels were not further increased by a high-fat diet. Increased activation of astrocytes
(glial fibrillary acidic protein (GFAP)+) and microglia (CD45+) has been described in
LDLr-/- mice.66
LDLr-/- mice exhibited impaired mitochondrial electron transfer chain activity in the
cerebral cortex, which showed an inverse correlation with blood cholesterol levels.61
They also showed glutathion depletion, changes in peroxide-removing-related enzymes
(such as glutathione peroxidase (GPx) and glutathione reductase (GR)) and increased
lipid peroxidation.61 LDLr-/- mice also had a decreased density of presynaptic terminals
in CA1 and dentate gyrus,67-68 suggesting reduced synaptic plasticity.
Cognitive and behavioral changes
As expected from the cellular changes in the hippocampus, LDLr-/- mice showed
spatial learning and memory impairments in the object location task when fed with
a normal as well as a cholesterol-enriched diet.61 In the MWM test, LDLr-deficient
mice showed impaired spatial memory with standard diet,67 while another study only
observed impaired memory in LDLr-deficient mice on a high-fat diet around the age
of 6 months.69 Also in working memory tests, such as the T-test or water radial-arm
maze, LDLr-deficient mice showed poorer performances.66-67
Studies on locomotor activity in LDLr-deficient mice have shown inconsistent results.
In one study LDLr-deficient mice showed increased locomotor activity compared to
WT mice in the open field,69 while in an earlier study no differences were observed.67
LDLr-deficient mice did not have increased anxiety as shown by prepulse inhibition
tests, acoustic startle reflex, the elevated zero maze and light/dark exploration.69 Highcholesterol-fed mice showed increased anxiety during light/dark exploration, but this
was true for both WT and LDLr-deficient mice.
Relation to Alzheimer’s disease
As in AD pathology, ApoE total RNA levels were decreased in LDLr-/- mice, while
ApoE protein levels were increased, both irrespective of the type of diet.62, 70 LDLr-/mice did not show any difference in brain Aβ40, Aβ42 or Aβ40/42 ratio with
chow, high-fat or high-cholesterol diet.62 There was no correlation between plasma
cholesterol levels and cerebral Aβ40 or Aβ42.
To investigate the effect of cholesterol levels or specific LDLr function in mice on
AD-like pathology, LDLr-deficient mice have been backcrossed with different AD
40
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Effect of CVD on brain structure and cognition
mouse models. Results of these studies are conflicting, showing either no effect or
increased amyloid plaque deposition.55, 70-71
In AD mouse models, LDLr deficiency influences memory deficits. At 13 months
of age, the spatial memory performance in the MWM was further decreased in the
amyloid precursor protein (APP)-overexpressing Tg2576 mouse when crossbred with
LDLr-/-.71 This effect was not yet present at 10 months of age. The MWM performance
at 13 months positively correlated with the cerebral amyloid load.71
2
Similar to ApoE-/- mice, LDLr-/- mice show increased inflammation, microvessel
abnormalities, reduction of synapses and cognitive impairment.65-67, 69 However, no
increased BBB permeability has been observed in young LDLr-/- mice (maximum 9
weeks),34 though older mice have not been studied.
LDLr-/-xApoB
Cerebral effects have been explored in two mouse models that combine the effect of
LDLr knockout and increased ApoB expression. The first model expresses human
ApoB in combination with LDLr knockout and is called LDLr-/-xhApoB, LDLr-/-;
Tg(ApoB+/+) or ATX,72-73 The second model is the LDLr-/- with Apobec1-/- knockout
and is called Ldlr-/-Apobec1-/- or ApoB100/LDLr-/-.74-75 Apobec1 is an enzyme in
the mouse liver that edits the mRNA of ApoB, creating the truncated ApoB48. By
knocking out this enzyme the concentration of the full-length ApoB100 will increase.
Both models are used as model for human familial hypercholesterolemia (FH).
These mice have increased levels of cholesterol, LDL and triglycerides, and show
atherosclerotic lesions on a normal standard diet.73, 75
LDLr-/-xhApoB
Although the LDLr-/-xhApoB mice have atherosclerotic lesions in the aorta and carotid
arteries after 6 months, no lesions have been observed in the large cerebral vessels at
these time points. It is however described (but not shown) that LDLr-/-xhApoB mice
at the age of 12 months have macroscopic atherosclerotic lesions at the bifurcations in
the circle of Willis.73 The cholesterol and fatty acid content in the cerebral arteries were
similar to WT mice at 3 and 6 months of age.76 In addition to atherosclerosis,
LDLr-/-xhApoB mice were hypertensive at 3 and 6 months of age.73, 76
In ATX mice, different aspects of vascular reactivity have been measured in vitro and
in vivo. In vivo, baseline CBF in the somatosensory cortex was reduced.73 The ex vivo
41
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measured myogenic tone (MT) was higher in cerebral arteries of ATX mice compared
to WT and increased with age. Endothelial dysfunction was apparent from a reduced
dilatory response to acetylcholine, lower sensitivity to wall shear stress and lower
flow-mediated dilatation, which was not affected by the NOS inhibitor L-NNA.73
As expected, CBF was correlated to the degree of flow-mediated dilatation. At least
part of the endothelial dysfunction appeared to be due to oxidative stress, as longterm treatment with the anti-oxidant catechin improved most of the above responses.
Contrary to the carotid arteries, the cerebral artery compliance actually increased in
ATX mice with age. A possible mechanistic explanation for this finding is that MMP-9
(though not MMP-2) activity was increased in the cerebral vessels of 6-month-old
mice, without changes in the cerebrovascular wall lipid composition, which typically
contribute to arterial stiffness.76
This data suggests that atherogenic mouse models affect CBF and endothelial function
in cerebral arteries, possibly without overt atherosclerotic lesions in the cerebral vessels.
Furthermore, as shown below, this might also influence cognitive function in these
mice. A direct casual link is however not provided.
ApoB100/LDLr-/Little is known about the neuropathology of ApoB100/LDLr-/- mice. While mature
aortic atherosclerotic lesions have been reported in old animals, it has not been
described whether these mice also have intracranial lesions. Histologically, astrogliosis
has been detected in the hippocampus, amygdala and several cortical areas. These mice
also showed a reduction of MAP2-positive dendrites, which was age-dependent in
the hippocampus, but only genotype-dependent in the lateral entorhinal cortex and
amygdaloidal basal nucleus.75 The MAP2 reduction indicates neuritic dystrophy and
may contribute to the cognitive decline discussed below.
Cognitive and behavioral changes
At the age of 6 months LDLr-/-xhApoB mice have a decreased learning capacity in the
MWM test compared to 3-month-old LDLr-/-xhApoB mice, while catechin improved
learning capacity.73 However, the escape latency and thus memory formation was not
affected in 6-month-old LDLr-/-xhApoB mice compared to WT or 3-month-old
LDLr-/-xhApoB mice.
The ApoB100/LDLr-/- transgenic mice showed impaired temporal episodic memory as
tested with the integrated memory test.75 Spatial memory was not impaired compared
to WT mice, but did decrease with age in both strains.
42
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Effect of CVD on brain structure and cognition
Interpretation of cognitive tests in these animals should be done with care as the mice
also had locomotor deficits, shown by shorter fall latencies in the rotarod test, reduced
strength in the grip strength test and reduction of rearing and increase of immobility
in the open field.75
2
Relation to Alzheimer’s disease
As early as at 3 months of age vascular Aβ deposits have been observed in the
ApoB100/LDLr-/- mouse, followed by deposits in the hypothalamus and cortical areas
at 18 months.75
All atherosclerotic mouse models that are discussed above have increased cholesterol
levels when fed a high-fat diet and exhibit atherosclerotic lesions in at least the
aorta. Before the age of 12 months no lesions were reported in the brain in any of
the models, although cerebral changes and cognitive impairment are already found
in younger animals. This suggests that there is no direct link between the extent of
intracranial atherosclerosis and cognitive function. Yet the kind of pathological changes
reported in each model differ a lot. Most models show an increase in inflammatory
response, although this has not been tested for hApoB-knock-in mice (see table 3).
Effects of atherosclerosis or the specific genes involved on endothelial function and
neurodegeneration have barely been tested, although endothelial dysfunction and
decreased number or function of neurons is suspected from the sparse results available.
Cerebral perfusion is only tested in ApoE-/- mice.
The effects on BBB permeability and Aβ deposition are not consistent between the
different models. Most likely the found effects are not only related to cerebrovascular
dysfunction, but also due to a direct effect of the gene in question on the pathways
involved in blood-brain barrier integrity or Aβ homeostasis. It is known, for example,
that ApoE can bind to Aβ and thereby increases Aβ deposition.77-78 Therefore, it will
be essential to investigate other (nongenetic) mouse models to unravel the mechanisms
involved.
Heart failure models
In humans, reduced cardiac output is associated with reduced cerebral perfusion,
brain abnormalities and cognitive impairment. There are several models of heart
failure in mice, ranging from acute to chronic models and genetic to surgery-induced
models. There is however no data on the cerebral effects in genetic models. Examples
43
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Bink DB Proefschrift 160218.indd 44
BBB: Blood-brain barrier; BDNF: Brain Derived Natriuretic Factor; CA/CRP: cardiac arrest/cardiopulmonary resuscitation; CBV: cerebral blood
velocity; LH: Left hemisphere; MWM: Morris water maze; NOR: Novel object recognition test; RH: Right hemisphere; PCA: posterior cerebral artery.
Differences compared to sham wild-type mice; n = number of animals per group
Table 4. Structural and functional brain changes in heart failure mouse models
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Effect of CVD on brain structure and cognition
of surgery-induced models are the aortic constriction, cardiac arrest and myocardial
infarction models (see table 4).
Transverse aortic constriction
The transverse aortic constriction (TAC) model is a mouse model of hypertension and
chronic heart failure. The constriction is effected by partial ligation of the aortic arch,
usually between both carotid arteries (see figure 1; TAC1 in table 4),79 but alternatively
2
Figure 1. Most commonly used models for atherosclerosis, heart failure and hypoperfusion to
study the effect of cardiovascular risk factors on the brain.
45
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CHAPTER 2
downstream of both carotids (TAC2 in table 4).80 Because the ligation between the
carotids (TAC1) is the most commonly applied model, we will discuss this type of
ligation in more detail.
TAC surgery induces hypertension, left ventricular (LV) hypertrophy and cardiac
failure with an acutely decreased LV ejection fraction, but a preserved LV ejection
fraction in the long-term.81-82 TAC mice have shown an increase in right carotid blood
flow and peak velocity from day 1 to 28.83-84 During this time window, the left carotid
peak velocity was decreased, although the blood flow was only reduced until day 7 and
returned to baseline after 14 days.83 One day after surgery the blood pressure in the
right carotid was approximately twice as high as in the left carotid,79 but no data are
available on the long-term effect of TAC on the blood pressure.
Cerebral perfusion and blood-brain barrier
TAC mice developed acute right hemisphere hypertension with increased cerebral
perfusion in the right hemisphere, while the perfusion was reduced in the left
hemisphere compared to sham-operated mice at day 1 and 7.79 At 3 or 8 weeks
after surgery the cerebral blood velocity was reduced in both hemispheres.85 BBB
permeability was increased at day 1 and 7 after surgery to the same extent in both
hemispheres despite the perfusion differences.79
Inflammatory response
In the first week after the surgery, an increase in superoxide production, NAD(P)H
oxidase activity, IL-1β and TNF-α mRNA expression and GFAP-positive cells was
observed in the cortex and hippocampus of both hemispheres.79 This shows that hyperand hypoperfusion may induce a similar cerebral inflammatory response.
Microglia were already activated at day one after TAC, and activation persists for at
least eight weeks along with increased cytokine levels.79, 85
Three and 8 weeks after ligation, the mice showed decreased GLUT-1 expression,
while GLUT-3 levels remained normal, indicating an imbalance in glucose supply to
the brain.85 Despite the perfusion differences and the inflammatory response, neuronal
death was not significantly increased after 3 or 8 weeks.85
Relation to Alzheimer’s disease
After 8, but not yet 3 weeks, Aβ deposits were visible. The microglial marker CD11b
colocalized with Aβ in the proximity of blood vessels, but not in the parenchyma.85
The cerebral amyloid deposition in cortex and hippocampus can be influenced by
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receptor for advanced glycation end products (RAGE).86 As early as four hours after
TAC, RAGE mRNA and protein levels were upregulated, most prominently in the brain
vessels. This increase was still present after 6 weeks in both hippocampus and cortex.
RAGE inhibition by knockout or pharmacological means and antioxidant treatment
(Tiron) reduced parenchymal Aβ deposits.86
2
Cognitive and behavioral changes
Only one recent study investigated the effect of TAC on cognition. This study
showed that TAC mice manifest cognitive impairment in the (spatial) memory
domain in the MWM test and Novel Object Recognition test.86 RAGE knockout and
pharmacological inhibition of RAGE, AGE or oxidants all protected against cognitive
impairment. This observation suggests that oxidative stress may play a crucial role in
inducing cognitive dysfunction. The effect of RAGE inhibition on cognition has also
been shown in the APPsw/0 Alzheimer mouse model.87
Myocardial infarction
Only two studies have described the cerebral effects after myocardial infarction (MI).
MI was induced by permanent ligation of the left anterior descending coronary artery
(LAD) resulting in a reduction of CBF after 4-6 weeks.88 The resting and myogenic
tone measured in proximal posterior cerebral arteries (PCAs) was increased ex vivo.
TNF-α expression was upregulated in the PCAs, localized to smooth muscle cells.
This study suggests that the TNF-α - Sphingosine (Sphk1) - sphingosine-1-phosphate
(S1P) pathway plays an important role in regulating the vascular tone.
Six weeks after ligation, the mice did not have a spatial memory deficit.88
These studies suggest that heart failure models such as TAC and MI lead to a reduced
CBF. Both models did not show (extensive) neurodegeneration in the relatively short
period studied. Increased inflammation is observed in all models, however only
vascular inflammation was investigated in the MI model. Inflammation appears to play
a crucial role in the pathology of these mice, as the reduction of specific inflammatory
factors normalizes CBF, vascular tone, Aβ deposition and cognition.
Cerebral hypoperfusion models
To directly study the effect of a reduced blood flow to the brain, hypoperfusion models
can be used. In these models either one or both carotid arteries are occluded or ligated.
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Table 5. Structural and functional brain changes in hypoperfusion mouse models
CHAPTER 2
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Table 5. Continued
2
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Bink DB Proefschrift 160218.indd 50
18F-FDG: Fluorodeoxyglucose; 8-arm: Eight-arm radial maze; BBB: Blood-brain barrier; CBF: Cerebral blood flow; CC: Corpus callosum; DA:
Dopamine; GFAP: Glial fibrillary acidic protein; ICH: Intracerebral hemorrhage; MBP: Myelin basic protein; OF: Open field test; ORT: Object
recognition task; PA: Passive avoidance; WML: White matter lesions. Differences compared to sham wild-type mice or to baseline measure; n =
number of animals per group
Table 5. Continued
CHAPTER 2
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The degree of hypoperfusion and cerebral changes depend on the number of carotids
that are ligated and the degree of ligation (see table 5).
Bilateral common carotid artery stenosis
Bilateral common carotid artery stenosis (BCAS) is a model for subcortical ischemic
vascular dementia89 and is copied from the chronic cerebral hypoperfusion rat model.90
Though in rats both carotid arteries can be fully occluded, the survival rate with full
occlusion is very low in mice. Therefore, BCAS mice are created by placing partially
occluding external microcoils around both carotid arteries (see figure 1). The severity
of the model can be modified by altering the diameter of the coils.
2
Cerebral perfusion and blood-brain barrier
With a coil diameter of 0.22 mm the CBF did not change. Smaller coils (0.20, 0.18 or
0.16 mm) did result in acute CBF reductions, with smaller coils having a larger effect.90
Most studies are performed with 0.18 mm coils due to the high mortality rate of
constriction with 0.16 mm coils (75%) compared to 0.18 mm coils (15%). The 0.18
mm coils led to a 60-70% reduction of the CBF after 2 hours compared to baseline,
and increased again gradually to approximately 72% after 1 day, 77% after 7 days, and
recovered to 80-85% of baseline after 1 to 3 months,89-91 while the blood pressure was
not affected.90-91
BBB permeability (measured by IgM and Evans blue extravasation) followed the
acute CBF changes, and increased in the white matter of BCAS mice after 3 days till
at least 14 days.92
Gray and white matter damage
White matter lesions (WML) were present at 14 and 30 days after placement of 0.20
mm, 0.18 mm and 0.16 mm coils90-91, 93-94 and did not differ in extent after 1 or 2
months of hypoperfusion.95 A reduction in myelinated fiber intensity was seen in the
corpus callosum, caudate putamen, internal capsule and to a lesser extend in the optic
tract.90 The WML score significantly correlated with the CBF reduction. Gray matter
changes were also reported after 30 days with the use of 0.16 mm coils, including
ischemic foci in the cerebral cortex, hippocampus and basal ganglia.90
In mice with 0.18 mm coils, the gray matter changes take longer to develop; after 30
days or 6 months no gray matter damage has been observed in most mice, but after 8
months pyknotic neurons are observed in the hippocampus and cerebral cortex.89-91, 96
In contrast, a different study reported neuronal perikaryal and axonal damage in few
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CHAPTER 2
mice already after 1 or 2 months.95 Atrophy was only observed in the hippocampus
and not in the cerebral cortex or corpus callosum. The CA1 and CA3 sectors were
more affected than the dentate gyrus as shown by the increased number of fragmented
or shrunken nuclei.89 BCAS mice also showed a reduction in cholinergic fibers, but no
difference in choline acetyltransferase-positive cells.
Inflammatory response
MMP-2-immunoreactive glial cells were increased as early as 3 days after BCAS and
deletion of the MMP-2 gene reduced severity of WML, BBB disruption and the
amount of inflammation.92 Increasing numbers of activated microglia were observed as
soon as 7 days after the operation.90, 93, 95 Increases in WM astrogliosis, microgliosis and
proinflammatory cytokines were mostly not yet observed after 7, but after 14 days.90,
94, 97
The exact mechanisms underlying the cerebral damage due to hypoperfusion are
not fully understood, but the rennin-angiotensin system and oxidative stress appear to
be involved. A study by Dong et al. demonstrated that cerebral hypoxia, inflammation,
WML and increase in renin, a blood-pressure regulating enzyme, induced by BCAS
can be improved by aliskiren (renin inhibitor) and Tempol (superoxide scavenger).97
Metabolism
Also metabolic abnormalities have been observed in BCAS mice. Two hours after BCAS,
the first 5-minute uptake of fluorodeoxyglucose (18F-FDG) was decreased in the
striatum and cerebral cortex; FDG uptake slowly recovered to 88% in the cerebral
cortex after 2 months. In contrast, in the hippocampus FDG uptake was initially
maintained (after 2 hours and 2 months), but was deteriorated after 6 months.89
Cognitive and behavioral changes
Working memory deficits have been observed with the 8-arm radial maze in BCAS mice
with 0.18 mm coils after 1, 2 and 5-6 months.89, 91, 95 Although reference memory
(8-arm radial maze) was not different after 30 days, it was impaired after 5-6 months
when tested with the Barnes maze. The number of revisiting errors correlated with
the CBF reduction from 7 till at least 28 days after BCAS surgery.98 Spatial reference
and serial spatial learning and memory measured with the MWM was not affected by
BCAS after 1 and 2 months.95
Other behavioral characteristics, such as sensory-motor reflexes or gating, nociception,
motor coordination, locomotor activity, behavioral despair and contextual or cued
fear conditioning did not show significant changes after 30 days.91 These findings
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Effect of CVD on brain structure and cognition
indicate that the working memory impairment after 30 days was not due to physical
characteristics, motor or sensory deficits. As with the observed histological damage,
the functional deficits become more pronounced as the hypoperfusion persists; after 3
months, locomotion and motor function were impaired.89
As said before, the extent of damage strongly depends on the severity of the model. In a
study with mice receiving an asymmetrical carotid stenosis (0.16 mm coil diameter left
and 0.18 mm right), it was nicely shown that moderate hypoperfusion results in a spatial
reference memory dysfunction in the hidden platform test. However, in more severely
affected animals, also the visual acuity and locomotion were affected,99 and in those cases
the outcomes of the MWM cannot only be attributed to cognitive function.
2
Relation to Alzheimer’s disease
In contrast to the TAC model, no Aβ deposits or axonal amyloid precursor
proteins have been detected in the hippocampus or cerebral cortex in WT mice
after 8 months.89
The combination of BCAS with APP overexpressing models has led to an accelerated
pathogenesis. The transgenic mouse model for cerebral amyloid angiopathy that
expresses human vasculotropic Swedish/Dutch/Iowa mutant a APP (called the
Tg-SwDI mice) is one of the widely used models for Alzheimer research. Microinfarcts
have been shown in a subset of Tg-SwDI mice with BCAS at 18-32 weeks, which were
not found at these ages in Tg-SwDI mice without BCAS or WT mice with BCAS.100
The Tg-SwDI mice also showed a more pronounced CBF decrease than WT mice
when subjected to BCAS. Furthermore, BCAS led to accelerated deposition of Aβ in
Tg-SwDI mice100 and in APPSwInd mice, a model expressing the Swedish and Indiana
APP mutations.101 The latter model also exhibited an increase in activated astroglia and
apoptotic cells 12 months after surgery.
In conclusion, BCAS mice have decreased CBF, increased inflammation and BBB
permeability, brain atrophy, WML, decreased metabolism and impaired cognition,
thus mimicking many aspects of vascular cognitive impairment in patients.
Other cardiovascular mouse models
Other relevant models are hypertension models and models for cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL). Hypertension is thought to be the most important cause for
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Table 6. Structural and functional changes in the discussed mouse models
cerebrovascular disease. There is however not much known about the cerebral effects of
chronic hypertension models. The most important findings are reduced CBF, increased
BBB permeability and other related vascular abnormalities (see supplemental table 2).
CADASIL is an inherited neurovascular disorder caused by mutations in the Notch3
receptor.102 It is a small vessel disease of the brain which causes recurrent ischemic
strokes with cognitive impairment and dementia.103-104 There are several genetic
mouse models for CADASIL; most with a mutation in the Notch3 gene. The specific
mutation and the expression level of Notch3 may determine the observed changes.105
Supplemental table 3 summarizes results for the three functionally active mutations
R90C, R169C and R170C. In addition, one mutated Notch1 mouse model has been
generated and assessed for cognitive function (see supplemental table 3). The different
CADASIL mouse models are reviewed elsewhere.104
Conclusions
Vascular cognitive impairment: which is the best model and why?
The optimal mouse model to study VCI should have similar pathophysiology as VCI
patients (face validity), comparable etiology (construct validity) and predict which
treatments do and do not have a therapeutic value (predictive validity).
Regarding the face validity, the animals should have reduced cerebral perfusion,
inflammation, BBB alterations, white matter lesions and cognitive deficits.3 The
animal models in this review are selected on having evident construct validity, i.e.
atherosclerosis, heart failure, hypertension or CADASIL. Since hypoperfusion
is associated with these diseases, hypoperfusion models represent an additional
interesting candidate model. Predictive validity should be an important condition
in future evaluation of the optimal animal model. However, as there are currently
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Effect of CVD on brain structure and cognition
no treatments known to be effective in VCI patients, it is not yet possible to test
the predictive validity. Endpoints on which predictive validity should be based are
cognition and as early endpoints inflammation, BBB alterations and white matter
lesions. In addition, a good model should ideally only represent one particular CVD
at a time, and be reversible by mechanical or pharmacological modulation. Only then
we can study the molecular and cellular mechanisms involved and assess whether the
cerebral damage and cognitive changes are reversible.
With the current knowledge the model that in our opinion best fulfils these criteria
is the BCAS model (see table 6), as it induces cerebral hypoperfusion, decreased
BBB integrity, cerebral inflammation, WML, decreased metabolism and cognitive
deficits. BCAS is the only CVD mouse model in which WML have been observed.
This surgery-induced model may be (partly) reversible, although no studies have
been published as yet where this is actually shown. A second advantage in contrast to
genetic models is the exclusion of possible developmental changes due to the genetic
manipulation. A third advantage is that in a later stage this surgery-induced model
can be combined with genetic models to study mixed pathologies, as has already been
done with AD models.
One disadvantage of the BCAS model is that it is very sensitive to the degree of ligation.
As discussed above, variations of 0.02 mm in coil diameter make the difference
between gray matter loss at 1 month after surgery or only after 8 months.
Furthermore, the visual performance may also be affected and needs to be tested to
exclude a confounding effect of damage in the visual pathway as seen in BCAS rats.
2
Alternatives to the BCAS model are two other operation-induced models, namely the
MI and TAC models. Since there is limited cerebral data for the MI model, it is not
known whether MI mice show all the relevant pathology and cognitive effects. The
cerebral effects of the TAC model are only studied by one experimental group and
reproducibility of the cerebral effects first has to be established. A potential drawback
is that TAC placement doesn’t always lead to LV hypertrophy and therefore cerebral
effects may be heterogeneous. This drawback can be prevented by selecting only
responsive mice based on the pressure gradient across the transverse aorta.106 White
matter lesions and long-term effects still have to be investigated in this model.
Atherosclerosis models may also be used to study CVD effects on cerebral perfusion,
structure and functioning. In models with a substantial atherosclerotic load, such
as in ApoE-/- and LDLr-/-xhApoB mice, (micro)vascular dysfunction has been
reported (see table 6). In milder atherosclerosis models data were not conclusive and
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Figure 2. Proposed flow chart of disease progression primarily based on experimental data of
the BCAS and TAC model. As not a lot of successive studies have been performed, no clear distinction
between cause and result of the different factors can be made.
different time points need to be tested. ApoE-/- is a commonly used model to study
atherosclerosis and AD. However, it is difficult to determine which effects are due to
the atherosclerosis and which are due to direct effects of ApoE on the brain through
e.g. Aβ clearance and deposition.107 Therefore, an atherosclerotic mouse model with an
intact ApoE gene is preferred.
In addition to the clean models summarized above, combinations of different models
are needed in a later stage to study additive or combined effects and to investigate
whether the different CVD have common mechanisms in creating cerebral changes
and cognitive effects. This knowledge is important for determining the molecular
targets for potential pharmacological treatments. These combined models will also
represent a great number of patients who have multiple risk factors and diseases.
The TAC model represents such a mixed model for hypertension and heart failure.
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Atherosclerotic models can be mixed with cerebral hypoperfusion models or with heart
failure models representing atherosclerosis in the end stage of the disease.
Also in AD research there is accumulating evidence that vascular dysfunction and
hypoperfusion play an important role in the pathogenesis of the disease.12, 108-109
Mixtures of AD models with CVD models are already studied in for example BCAS
and LDLr-/- mice, showing aggravated pathology, CBF reduction and cognitive
dysfunction.71, 100-101
2
Mechanistical insides and future directions
As our review clearly shows that the available data on mouse models to study VCI are
diverse we need to define a standard set of measurements in each candidate model
which is to be tested at different time points. This set needs to include data on
cerebral perfusion, microvascular inflammation, white matter lesions, BBB integrity
and behavior (especially cognition).3 Different time points are needed to unravel the
sequence of events (see figure 2).
Besides cognitive tests, behavioral tests such as motor function and anxiety should
be performed in all animal models to ensure that the results of cognitive tests are not
affected by locomotion or anxiety. Moreover, multiple cognitive tests studying different
cognitive domains should be included to study the specific cognitive phenotype.
Besides causal and pathological differences, VCI and AD patients may have different
clinical phenotypes. VCI patients tend to have more severe impairment in executive
functions compared to AD patients.110 However, results are not consistent111 and it
is not yet possible to make a clear distinction based on clinical phenotype. In animal
models generally only learning and memory is tested while other cognitive deficits are
frequently neglected. Because memory impairment is not required for the diagnosis
of VCI and other cognitive deficits may be more important in VCI, it is important to
extend the behavioral and cognitive test battery in these animal models.
Cerebral perfusion should be a key feature in future studies, but has yet not been
measured in many models. In vivo techniques to study cerebral perfusion are MRI,112
SPECT,113 laser Doppler flowmetry,90, 99 laser speckle flowmetry,114 CT,115 diffuse
correlation spectroscopy116 and two-photon microscopy.117 There are however great
differences between methods in the sensitivity, area size, location and spatial resolution.116
BBB integrity can be examined in vivo by contrast-enhanced MRI. Histologically, the
permeability is assessed by the presence of larger molecules, such as albumin, IgG or
Evans Blue, that only penetrate the brain in case of increased permeability.41, 79 More
subtle damage can be detected by analyzing the microvascular structure.105
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Measuring white matter damage is problematic because of the small amount of white
matter in rodents. However, in the BCAS model it has been shown that it is possible
to reproduce the finding of WML in mice by multiple groups.90, 94, 118
Inflammation is a key pathological feature in VCI and is involved in several other
neurodegenerative diseases such as AD.3, 119-120 All CVD mouse models that have been
discussed in this review show an increase in inflammation. In both the ApoE-/- and
the TAC model, an inflammatory pathway has shown to be a primary factor in the
cerebral pathology. A key player across all the models discussed is MMP-9. MMP-9
may be activated directly through the pro-inflammatory CypA – NF-κB –MMP-9
pathway.36 Alternatively, RAGE and the TNF-α – Sphk1 - S1P pathway have also
been show to be important for heart failure in mouse models,86 88 and both are
known to influence MMP-9 activity.121-122 Increased MMP-9 activity has also been
found in LDLr-/-xhApoB and the heart failure model CA/CRP.76, 123 Both RAGE and
MMP-9 have been implicated in human studies of VaD and AD.124-126 MMPs are also
known for their influence on neuronal loss and synaptic plasticity.127-129 Altogether,
inflammation appears to be one of the key processes present at the beginning of the
pathology leading to cognitive impairment as a consequence of CVD.
Cerebral hypoperfusion may indeed be a key trigger to inflammation and cognitive
impairment.12, 89-90 Cerebral hypoperfusion is associated with VCI, improvement
of brain perfusion in humans leads to an improvement of cognitive function
and, intriguingly, the induction of cerebral hypoperfusion in mice leads to a VCI
phenotype. However, the mechanisms underlying these observations remain largely
elusive as most factors are interrelated and more time points need to be studied in
the different mouse models to clearly dissect the mechanisms involved and the order
of events in the disease progression (figure 2). Since there is accumulating evidence
that vascular dysfunction and hypoperfusion also play an important role in AD, and
mixtures of AD models with CVD models like BCAS and LDLr-/- mice significantly
increase the progression of the disease progression, this research will not only be
important for the pure VCI and VaD syndromes, but will have a much larger impact
on our understanding of neurodegenerative diseases.
Disclosure/Conflict of Interest
The authors declare no conflict of interest.
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Supplementary tables
Supplementary table 1: Excluded studies
Studies fulfilling the criteria of: 1) Publication in peer-reviewed journal, 2) Blinded assessment of
outcome, 3) Sample-size calculation, 4) Compliance with regulatory requirements, 5) Statement conflict
of interest, 6) Randomization, 7) Avoidance of anesthesia, 8) Control of physiological variables
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ACh: Acetylcholine; BBB: Blood-brain barrier; CBF: Cerebral blood flow; Ch: choline; DA: Dopamine; ICH: Intracerebral hemorrhage; WML: White
matter lesions. Differences compared to (vehicle treated) wild-type mice; n = number of animals per group
Supplementary table 2: Structural and functional brain changes in hypertension mouse models
Effect of CVD on brain structure and cognition
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BBB: Blood-brain barrier; CBF: Cerebral blood flow;morrhage; GFAP: Glial fibrillary acidic protein; GOM: Granular osmiophilic material; SMC:
Smooth muscle cell; WM: White matter. Differences compared to wild-type mice; n = amount of animals per group
Supplementary table 3: Structural and functional brain changes in CADASIL mouse models
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Effect of CVD on brain structure and cognition
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