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Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
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Neurovascular dysfunction and neurodegeneration in dementia and
Alzheimer's disease
Amy R. Nelson, Melanie D. Sweeney, Abhay P. Sagare, Berislav V. Zlokovic
Department of Physiologyand Biophysics and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA
abstractarticle info
Article history:
Received 14 October 2015
Received in revised form 10 December 2015
Accepted 10 December 2015
Available online xxxx
Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment,
and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the patho-
physiological events leading to cerebral blood ow dysregulation and disruption of the neurovascular unit and
the bloodbrain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's dis-
ease (AD). Particularly, we examine the link between neurovascular dysfunction andneurodegeneration includ-
ing the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β
peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels,
which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental
treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be
addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive
Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock
© 2015 Elsevier B.V. All rights reserved.
Keywords:
Alzheimer's disease
Dementia
Neurovascular unit
Bloodbrain barrier
Vascular factors
Neurovascular medicine
1. Introduction
Blood vessels in the brain deliver essential nutrients to and remove
metabolic waste products from the central nervous system (CNS) [1].
Although the human brain makes up only 2% of total body mass, it
consumes 20% of the body's oxygen and glucose supply [2].Proper
regulation of cerebral blood ow (CBF) is critical for brain health and
survival. Loss of CBF halts brain functions in seconds and causes perma-
nent brain damage within minutes [3]. CBF is precisely regulated by
the neurovascular unit (NVU) to assure that brain energy demands are
met [1,4]. The NVU is comprised of several cell types including vascular
cells (endothelial cells, pericytes, and vascular smooth muscle cells
(VSMCs)), glia (astrocytes, microglia, and oligodendrocytes), and neu-
rons [1]. A schematic representation of the NVU at the level of brain
capillaries is shown in Fig. 1.
The bloodbrain barrier (BBB) is part of the NVU that prevents un-
controlled entry of blood-derived products and pathogens into the
brain and mediates the exchange of molecules into and out of the
brain parenchyma via a specialized substrate-specic transport system
expressed in brain endothelium [1,5]. The BBB is quite unique when
compared to the highly permeable systemic capillaries that permit the
transport of larger molecules across the vessels and into peripheral tis-
sues [6]. Brain capillary endothelial cells are connected by tight and
adherens junction proteins (e.g., claudin, occludin, junction adhesion
molecules, and cytoplasmic accessory proteins including zonula oc-
cludens (ZO) 1, 2, 3, cinguilin, and others), forming a continuous endo-
thelial monolayer. This anatomical barrier permits the passage of only
small circulating lipid-soluble molecules (b400 kDa) with less than
nine hydrogen bonds into the brain, and allows the free exchange of ox-
ygen and carbon dioxide [1]. The BBB isolates braininterstitial uid (ISF)
and cerebrospinal uid (CSF) compartments from the plasma compart-
ment, and thus prevents the entry of many blood-derived molecules
into brain parenchyma [4]. The movement of large molecules across
the BBB including proteins and peptides is only possible via highly spe-
cialized transport systems expressed in brain endothelium [79].Inthe
human brain, there is an estimated 400 miles total length of capillaries
with about 20 m
2
of microvascular surface area available for molecular
transport [10]. This makes the BBB the largest exchange transport sur-
face area in the brain and the major clearance pathway for potentially
neurotoxic molecules that are produced and/or accumulate in the
brain, as for example, Alzheimer's toxin amyloid-βpeptide (Aβ)[11].
It is becoming increasingly apparent that cerebrovascular dysfunc-
tion contributes to dementia and AD [1,1216], as well as other neuro-
degenerative disorders such as amyotrophic lateral sclerosis (ALS) [17],
Parkinson's disease (PD) [18], and Huntington's disease (HD) [19].NVU
disruption and BBB breakdown can lead to entry of circulating neuro-
toxic molecules into the brain, faulty clearance of neurotoxic molecules
from brain to blood, improper energy metabolite and nutrient delivery,
and abnormal expression of growth factors, matrix molecules, and
Biochimica et Biophysica Acta xxx (2015) xxxxxx
This article is part of a Special Issue entitled: Vascular Contributions to Cognitive
Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna
M. Wilcock
Corresponding author at: Zilkha Neurogenetic Institute, 1501 San Pablo Street,
Los Angeles, CA 90089, USA.
E-mail address: zlokovic@usc.edu (B.V. Zlokovic).
BBADIS-64389; No. of pages: 14; 4C: 2, 3, 5
http://dx.doi.org/10.1016/j.bbadis.2015.12.016
0925-4439/© 2015 Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
journal homepage: www.elsevier.com/locate/bbadis
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
vascularreceptors, which all mayeventually lead to synaptic and neuro-
nal dysfunction [4]. Here, we review the cellular and molecular mecha-
nisms in cerebral blood vessels leading to neurodegeneration including
the effects of genetic risk factors for AD on cerebrovascular functions
and Aβclearance, and the impact of vascular risk factors, environment
and lifestyle on cerebral blood vessels. Finally, we discuss potential ex-
perimental treatments for dementia and AD based on the neurovascular
model and review some critical questions in the eld to be addressed by
future studies.
2. Alzheimer's disease
AD is the most common form of dementia that currently affects 5.3
million Americans [20]. The majority of cases are sporadic late-onset,
and b5% of cases are early-onset autosomal-dominant AD (ADAD)
[21]. Pathological hallmarks of AD include elevated brain parenchymal
and vascular Aβ, hyperphosphorylated neurobrillary tau tangles,
gliosis,and neuronal loss [1].Mounting evidence demonstrates that vas-
cular dysfunction contributes to dementia and AD [1,14,15]. Vascular
risk factors (e.g., hypertension, diabetes) and some major genetic risk
factors for AD (e.g., apolipoprotein E ε4(APOE4)) lead to cerebrovascu-
lar damage [1,4,20], and cerebrovascular disorders associated with AD.
Elucidating the mechanisms underlying vascular pathophysiology to
aid in identifying novel therapeutic targets for AD has been declared a
national research priority [14,15].
2.1. The two-hit vascular hypothesis
The two-hit vascular hypothesis of AD states that cerebrovascular
damage (hit 1) is an initial insult that is self-sufcient to initiate neuronal
injury and neurodegeneration but can also promote accumulation of
Alzheimer's Aβtoxininthebrain(hit 2)(Fig. 2)[2225,1,16]. Cerebrovas-
cular disruption including BBB breakdown and resting CBF reductions can
lead to accumulation of neurotoxic circulating molecules (e.g., thrombin,
plasminogen, brinogen) and hypoperfusion in the brain, respectively,
that can directly initiate neuronal injury [1,23]. Vascular dysfunction
can also inuence the amyloidogenic pathway to diminish Aβclearance
and increase Aβproduction leading to elevated Aβlevels in the brain
[1,11].Thus,theAβ-independent and Aβ-dependent pathways interact
and can independently and/or synergistically lead to the onset and pro-
gression of AD dementia. Importantly, both pathways are impacted by
vascular, genetic, environment, and lifestyle risk factors.
2.2. AD genetic risk factors with vascular links
Age is the number one risk factor for AD, but genetic risk factors also
have a signicant effecton the AD disease process.Vascular implications
are now known for several of AD genetic risk factors and are emerging
for additional risk genes, as discussed below.
2.2.1. APOE4
APOE is a 34 kDa glycoprotein that is primarily produced by astro-
cytes in the brain and by the liver in the periphery and is important
for lipid metabolism [26]. In humans, there are three alleles of APOE:
APOE2,APOE3,andAPOE4.APOE4 is the strongest and most highly repli-
cated risk factor for late-onset sporadic AD [21,27]. An individual's risk
of AD is increased 3.7 times in carriers of a single APOE4 allele and 12
times in carriers of two APOE4 alleles, compared to APOE3 carriers [28].
APOE4 increases BBB damage, cerebral amyloid angiopathy (CAA),
and brinogen deposits in human brain [2933]. Furthermore, young
APOE4 carriers with no memory impairment have reduced cerebrovas-
cular reactivity in response to a memory task and carbon dioxide inha-
lation [34].APOE4 carriers have accelerated pericyte degeneration and
BBB breakdown, compared to APOE3 carriers, that is likely related to
the activation of cyclophilin A (CypA)-matrix metalloproteinase-9
(MMP-9) pathway in blood vessels, particularly in pericytes [28,29].In
agreement with these ndings, APOE4 transgenic mice exhibit activa-
tion of the CypA-NFκB-MMP-9 pathway in pericytes that was demon-
strated to result in degradation of BBB tight junction and basement
membrane proteins causing BBB disruption [35]. However, APOE2 and
APOE3 expressing transgenic mice have an intact BBB compared to
APOE4 mice [35,36] and are able to suppress the CypA-NFκB-MMP-9
BBB-degrading pathway in pericytes [35].
Furthermore, APOE isoforms differentially affect binding and clear-
ance of Aβ, where APOE2-AβNAPOE3-Aβcomplexes bind to a major
Aβclearance receptor the low-density lipoprotein receptor-related pro-
tein 1 (LRP1) at the abluminal side of the BBB and are rapidly cleared
across the BBB into circulation, whereas APOE4-Aβcomplexes interact
poorly with LRP1 and are removed from the brain by the much slower
and less efcient very low-density lipoprotein receptor (VLDLR) clear-
ance mechanism [37,38]. Thus, impaired Aβclearance byAPOE4 relative
to APOE3 or APOE2 may ultimately accelerate Aβaccumulation in the
brain.
2.2.2. PICALM
PICALM encodes the phosphatidylinositol-binding clathrin assembly
protein that is involved in endocytosis and internalization of cellrecep-
tors and intracellular trafcking of endocytic proteins [3941]. PICALM
is highly expressed in the brain capillary endothelium lining the BBB
[41]. Approximately 20 single nucleotide polymorphisms (SNPs) in
the noncoding region of PICALM have beenassociated with AD in several
genome-wide association studies (GWAS) [21,42,43].Recently,themo-
lecular mechanism by which PICALM normally inuences Aβclearance
across the BBB has been elucidated in an in vitro human model of the
BBB [41].Briey, it has been shown that Aβbinding to LRP1 at the
abluminal side of the BBB recruits PICALM and initiates rapid PICALM/
clathrin-dependent endocytosis of Aβ-LRP1 complexes. PICALM then
continues to guide trafcking of Aβ-containing endocytic vesicles across
brain endothelium fusing sequentially with Rab5 and Rab11 and ulti-
mately leading to intracellular transport and exocytosis of Aβ, respec-
tively, at the luminal side of the BBB thus completing Aβtranscellular
transport and clearance across the BBB [41]. Importantly, PICALM levels
are reduced in AD brain endothelium, which correlates with elevated
Aβlevels, Braak stage, and the level of cognitive decline as shown by a
recent neuropathological study [41]. Furthermore, induced pluripotent
stem cell (iPSC)-derived human endothelial cells carrying the protective
allele of the rs3851179 PICALM variant have higher PICALM expression
and increased Aβclearance [41].Similarly,micedecient in brain endo-
thelial Picalm develop accelerated Aβaccumulation in the brain and be-
havioral decits, which all can be reversed by endothelial-specic
expression of Picalm [41]. Altogether, these data support the view that
PICALM controls Aβtransport and clearance across the BBB and there-
fore could have a strong vascular link to AD.
Fig. 1. The neurovascularunit (NVU) at the level of braincapillary is comprised of vascular
cells (pericytes and endothelial cells), glia (astrocytes,oligodendrocytes, and microglia),
and neurons.
2A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
2.2.3. CLU
Clusterin (CLU), also known asapolipoprotein J (APOJ), is a disulde-
linked heterodimeric glycoprotein composed of an α- and β-subunit
that aids in Aβclearance [37]. Recent GWAS studies have identied a
SNP within CLU on chromosome 8p21.1, rs11136000, that is signicant-
ly associated with sporadic AD [21,42,44]. The C allele is considered an
AD risk factor; whereas the minor T allele has a protective effect and
reduces the risk of AD by 16% [42,44]. Individuals with the CLU
rs11136000 risk C allele exhibit reduced white matter integrity and hy-
peractivation of the prefrontal andlimbic areas during working memory
tasks, as determined recently via diffusion tensor imaging magnetic res-
onance imaging (DTI-MRI) and functional MRI, respectively [45]. CLU
binds to several different proteins including Aβand has been shown
to prevent aggregation and promote clearance of Aβpeptides across
the BBB [37]. More specically, Aβ42 bound to CLU can be cleared rap-
idly across the BBB via LRP2 as shown in a murine model [37,46].
2.2.4. PSEN
Presenilin 1 (PSEN1) and PSEN2 genes encode presenilins 1 and 2,
respectively, that act as aspartyl proteases to facilitate γ-secretase
cleavage of Aβprecursor protein (APP) to produce Aβ[21]. Many
PSEN mutations have been identied in ADAD including 185 mutations
reported in PSEN1 and 13 mutations in PSEN2 [21].Mostofthese
mutations increase the ratio of Aβ42:Aβ40 in the brain [21]. However,
PSEN1 mutations also lead to major cerebrovascular pathology in
humans including disruption of small cerebral blood vessels, degenera-
tion of pericytes and mural cells, BBB breakdown, and Aβdeposits in
small cerebral arteries, arterioles, and capillaries [47,48].Similarly,
prominent cerebrovascular pathology with BBB breakdown, character-
ized by microhemorrhages, thinned and irregular microvessels, string
vessels, a thickenedbasement membrane, and a reduction in hippocam-
pal microvascular density have been shown inPSEN1 transgenic models
[49,50].
2.2.5. APP
There are 24 reported mutations in APP in ADAD subjects and, like
PSEN mutations, mostly result in an increased Aβ42:Aβ40 ratio in the
brain [21]. Patients with hereditary CAA of the Dutch, Iowa, Arctic,
Flemish, Italian, or Piedmont L34V vasculotropic mutations in APP
have degeneration of VSMCs leading to hemorrhagic strokes and de-
mentia [1,4,16]. Furthermore, duplication of the gene encoding APP
causes ADAD with CAA and intracerebral bleeding [1].
2.2.6. MEOX2
Mesenchyme homeobox gene 2 (MEOX2), a transcription factor
expressed solely in the vasculature in brain, regulates vascular cell dif-
ferentiation and remodeling [51]. A GWAS study using high-resolution
Fig. 2. The two-hit vascular model of Alzheimer's disease (AD)dementia. Vascularfactors, suchas hypertension anddiabetes, and/orgenetic risk factorsfor AD, such as apolipoproteinE ε4
(APOE4), can all lead to cerebrovascular damage (hit1; green boxes). Within the amyloid-βpeptide (Aβ)-independent pathway, cerebrovascular damage leads to bloodbrain barrier
(BBB) dysfunction and accumulation of blood-derived neurotoxic molecules in the brain, from one hand, and oligemia or reduced cerebral blood volume, from the other. Additionally,
within the amyloidogenic Aβpathway, BBB dysfunction can disrupt Aβclearance across the BBB and oligemia leads to overexpression and enhanced processing of Aβprecursor protein
(APP), which both can promote Aβaccumulation in the brain (hit 2; black boxes). The converging Aβ-independent and Aβ-dependent pathways can each independently and/or syner-
gistically lead to synaptic and neuronal dysfunction, neurodegeneration, and disruption of brain structural and functional connectivity that ultimately leads to dementia.
3A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
array comparative genomic hybridization found a copy number variant
in MEOX2 in ADAD subjects [52]. Furthermore, brain endothelial cells
from AD subjects express very lowlevels of MEOX2 which lead to vessel
regression, LRP1 proteosomal degradation, and reduced Aβclearance
across the BBB, all of which were reversed by restoring MEOX2 endothe-
lial expression [53]. Transgenic mice with a single allele of Meox2 devel-
op cerebral endothelial hypoplasia with reduced brain perfusion and
impaired Aβefux caused by reduced LRP1 expression [53].
3. Cerebrovascular dysfunction in AD
Vascular damage and dysfunction are frequently associated with
neurodegeneration and contribute to AD [1,2,12,15,54,55].Someindica-
tors of BBB breakdown include accumulation of blood-derived proteins
and cells in the brain and CSF, loss of pericytes and endothelial tight
junction molecules, microbleeds, and alterations in BBB Aβtransporter
expression (e.g., receptor for advanced glycation end-products (RAGE)
and LRP1). Some key pathophysiological, cellular, and molecularmech-
anisms leading to cerebrovascular dysfunction in AD are discussed
below.
3.1. Diminished CBF and neurovascular uncoupling
The brain microvasculature regulates its local capillary blood ow by
maintaining a delicate balance between the anti-thrombotic and pro-
thrombotic pathways within the capillary network, which normally
prevents intra-vascular coagulation and allows blood to ow [56].Re-
gional CBF responses are normally controlled by local neuronal activity
within the NVU modules, a process known as neurovascular coupling
[2]. A number of studies have shown reductions in resting CBF in
aged cognitively normal individuals that are at risk of developing
AD [1,2,57] and in AD patients [1,2,58], as well as CBF dysregulation
[2,54]. The CBF reductions may occur prior to cognitive impairment in
humans [57] and were also found in APP transgenic models of AD [59]
and pericyte decient murine models [60].
VSMCs derived from small cerebral penetrating arteries critically
regulate CBF to the brain [2]. Recent studies have shown a hypercon-
tractile phenotype of VSMCs derived from small arteries in AD and AD
models characterized with accumulation of several contractile proteins
directed by elevated activity of the serum response factor (SRF)/
myocardin tandem of transcription factors caused by hypoxic changes
[61]. Arterial hypercontractility and impaired ability to relax can in
turn diminish arterial supply of blood to the brain, which reduces CBF
and creates a chronic brain hypoperfusion state that may contribute to
dementia by several pathways as discussed below.
In addition to the hypercontractile phenotype, arterial VSMCs in AD
also exhibit a greatly redu ced ability to clear Aβ, which leads to accumu-
lation of Aβin the vessel wall causing CAA [62] that in turn further
aggravates CBF reductions and may promote cerebral microbleeds. Re-
cent experimental studies have suggested that in addition to a major
role of VSMCs in controlling CBF [2,63],CBFcanalsoberegulatedat
the capillary level by pericytes, particularly during experimental cere-
bral ischemia that leads to constriction of pericytes obliterating capillary
blood ow during thereperfusion phase [64]. This eventually can lead to
pericyte cell death and degeneration, resembling pericyte degeneration
seen in AD and other neurodegenerative disorders [1719]. However,
whether pericytes play a similar role in human disease as shown in
animal models remains to be addressed by future studies.
Mild chronic hypoperfusion, known as oligemia, can lead to a delete-
rious chain of events in neurons by impairing neuronal protein synthe-
sis that is required for synaptic plasticity, a process critically involved in
learning and memory [65]. Additionally, CBF reductions diminish oxy-
gen delivery to brain that favors anaerobic brain metabolism, which in
turn diminishes ATP synthesis required for the maintenance of the sodi-
um pump or Na
+
,K
+
-ATPase activity that regulates ion distribution in
neurons necessary for proper ring of action potentials and normal
neuronal excitability [2]. Hypoperfusion also leads to imbalances in
pH, electrolytes, and water gradients which lead to edema, white matter
lesions, and ultimately, neuronal death [1].
3.2. BBB breakdown
Regional BBB permeability in the living human brain duringnormal
aging and in mild dementia patients was recently assessed quantitative-
ly using an advanced dynamic contrast-enhanced (DCE)-MRI method
[12]. This study has shown that BBB breakdown in the hippocampus in-
creases in an age-dependent manner, worsens in individuals with mild
dementia [12], and corresponds with increases in CSF levels of pericyte
injury marker, soluble platelet-derived growth factor receptor-β
(sPDGFRβ)[12,66].Reective of BBB breakdown, the CSF-to-plasma-al-
bumin ratio is also increased in AD patients particularly in those with
vascular risk factors [67], as well as in individuals with mild dementia
or mild cognitive impairment (MCI) [12] and in cognitively normal
APOE4 carriers at genetic risk for AD [29].
In post-mortem studies, an accumulation of blood-derived proteins
including brinogen, thrombin, plasminogen, immunoglobulin G, and
albumin were found in the hippocampus and cortex of AD subjects
[3032,68,69], which was associated with pericyte degeneration [30,
6973]. MRI studies reveal microbleeds and iron accumulation in the
brain of patients with preclinical AD [74] and AD [33,75,76],especially
in the hippocampus [77]. In a cohort of 174 patients, lobar microbleeds
were identied in 40% of AD subjects and 24.3% of MCI patients using
susceptibility-weighted imaging (SWI) MRI [74]. The incidence of
lobar microbleeds was positively associated with age, APOE4 carrier
status, and Aβburden, as measured by (11)C-labeled Pittsburgh
Compound-B positron emissiontomography (PIB-PET) [74]. Additional-
ly, multiple lobar microbleeds were associated with lacunar infarctions
and severity of white matter hyperintensities [74]. Also, in a recent
study that included 148 AD patients, 44.6% of the patients exhibited
brain microbleeds [75]. Furthermore, the patients with a high number
of microbleeds had several associated vascular risk factors including
diabetes and hypertension [75]. Microbleeds measured by SWI-MRI
and/or T2*-weighted MRI were also found in 22% of 1504 studied de-
mentia patients [76]. The microbleeds positively correlate with age,
sex (microbleeds occur more frequently in males), and hypertension,
and negatively with Mini-Mental State Examination (MMSE) cognitive
score [76].
Pericyte injury and/or loss has been identied by post-mortem anal-
ysis in many neurodegenerative diseases including AD [30,69,71,72] as
well as by CSF analysis of living MCI patients [12]. Degenerating
pericytes accumulate intracellular inclusions, pinocytic vesicles, and
large lipid granules and show mitochondrial abnormalities [71,72].
These microstructural changes in pericytes correlate with capillary re-
ductions, dilation of vessels and the appearance of tortuous vessels
[71]. Simplied schematics of normal BBB and BBB breakdown with
neurovascular pathways leading to neurodegenerative changes are
illustrated in Fig. 3.
3.3. Reduced glucose utilization
Glucose transporter 1 (GLUT1) oncerebral microvessels is decreased
in post-mortem AD brain tissue [78]. GLUT1, encoded by SLC2A1,isthe
major transporter of glucose across the BBB from the blood to the brain
[1,4,79]. Cognitively normal individuals with genetic riskfor AD or pos-
itive AD family history [80] and mild or no cognitive impairment that
later develop AD [81] all have reduced glucose utilization in the
hippocampus, parietotemporal cortex, and/or posterior cingulate cortex
measured by 2-[
18
F]-uoro-2-deoxy-D-glucose (FDG)-PET, which oc-
curs prior to brain atrophy and neuronal dysfunction [80].Brainglucose
uptake correlates with the level of GLUT1 on cerebral microvessels [82].
In addition to glucose transport, GLUT1 is also critical for the mainte-
nance of proper brain capillary networks, CBF, and BBB integrity, as
4A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
demonstrated in humans with SLC2A1 mutations [83] and Slc2a1 trans-
genic mice [79] which contributes to neurodegeneration and behavioral
decits in murine model of AD and GLUT1 deciency [79].SeeFig. 3.
3.4. Aβclearance
In sporadic AD, faulty Aβclearance, rather than increased Aβpro-
duction, is thought to promote elevated brain Aβlevels [84]. Experi-
mental studies in multiple animal models have shown that under
physiological conditions, 7085% of Aβis cleared fromthe brain primar-
ily by transvascular clearance across the BBB and a small portion is re-
moved by ISF bulk ow [11,85,86]. The primary receptor mediating
BBB transcytosis of Aβis the LRP1, that is expressed mainly at the
abluminal side of the BBB [1,4,11,41,86,87].Aβbound to endothelial
LRP1 is rapidly internalized by PICALM at the endothelium, which medi-
ates PICALM/clathrin-dependent endocytosis of Aβ-LRP1 complexes by
endothelium and guides trafcking of Aβ-containing endocytic vesicles
towards exocytosis ultimately leading to Aβtranscytosis [41],as
discussed above. Additionally, a soluble form of LRP1 (sLRP1)is generat-
ed by proteolytic cleavage of LRP1 by β-secretase and circulates in the
plasma binding and sequestering free Aβ40 and Aβ42 and transporting
them via blood to the liver and kidney for removal from systemic circu-
lation [11,86]. See Fig. 3Ainset.
3.4.1. LRP1
In normal aging and AD, there is a signicant reduction in LRP1
expression in brain endothelial cells [88] and VSMCs [62]. A decrease
of LRP1 on microvessels negatively correlates with an increase of Aβ
in brain [88].SeeFig. 3B inset. High levels of SRF and myocardin in
VSMCs [61,62] lead to elevated expression of sterol response element
binding protein 2 (SREBP2), a major LRP1 transcriptional suppressor,
that leads to LRP1 depletion and thereby reduced Aβclearance across
Fig. 3. Bloodbrain barrier (BBB) pathwaysto neurodegeneration in dementia and Alzheimer's disease (AD). A. In the normal capillary, there is an intact BBB composed of tightly joined
endothelial cells and supported by mural pericytes, as shown in this simplied schematic. The BBB normally selectively regulatesthe passage of moleculesfrom blood to brain and vice
versa, and restricts entry of blood-derived products and toxins into the brain. There are many transporters and receptors along the BBB that permit molecules to cross the BBB via sub-
strate-specic transport systems, some of which are particularly relevant to AD pathophysiogenesis, as illustrated in the inset. For example, the normal BBB has high expression of the
glucosetransporter (GLUT1), moderateexpression of low-density lipoprotein receptor-related protein-1(LRP1), and minimal expression of receptor for advanced glycation end-products
(RAGE). B. In the AD capillary, there is a vicious cascade of events that can lead to neurodegeneration, as shown in this schematic and described as follows. 1. Pericytes degenerate and
detach. 2. The BBB becomes leaky. 3. Blood-derived molecules like brinogen, thrombin, and plasminogen leak from vessels and are directly toxic to neurons and can further induce
BBB damage. Erythrocyte extravasation induces accumulation of hemoglobin-derived iron which causes generation of reactive oxygen species (ROS) and oxidative stress to neurons,
and albumin promotes local tissue edema. 4. BBB transporter expression is altered,e.g., LRP1 and GLUT1 expressions are signicantly reduced, whereas RAGE expression is increased.
The alterations in LRP1 and RAGE reduce the clearance and increase the uptake of Aβinto the brain, respectively, leading to Aβaccumulation in the brain. Also, normal cerebrovascular
functions are disrupted by vascular pathologies including 5. Cerebral amyloid angiopathy, 6. Damaged and thickening of the basement membrane, and 7.Stringvessels.
5A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
the BBB [24]. Oxidation of surface LRP1 and sLRP1 prevents them from
binding Aβand thus limits the efcient efux of Aβfrom the brain
[89,90].
3.4.2. RAGE
RAGE is the major Aβinux receptor at the BBB that transports Aβ
from the blood into the brain [4,11,91]. RAGE is normally expressed at
low levels at the BBB, but its expression is increased in normal aging
and in AD brain endothelium and is associated with increased cerebro-
vascular and brain accumulation of Aβ[9193]. See Fig. 3B inset.
3.5. Concomitant vascular abnormalities
CAA, basement membrane abnormalities, string vessel formation,
microinfarcts, arteriosclerosis, and/or atherosclerosis are frequently ob-
served in MCI and AD patients [94] and in post-mortem AD brain tissue
[95]. Brain microvasculature is structurally altered in AD and other neu-
rodegenerative diseases and some of these vascular abnormalities are
discussed below.
3.5.1. Cerebral amyloid angiopathy
CAA is the deposition of amyloid along the cerebrovasculature that
occurs in both familial ADAD and sporadic AD (Fig. 3B). Patients with
hereditary Dutch, Iowa, Arctic, Flemish, Italian, or Piedmont L34V
vasculotropic mutations develop CAA followed by rupture of blood
vessels and hemorrhagic strokes in midlife [1,4,16]. CAA is known to
worsen AD pathology and occurs in 80% of AD patients [1]. CAA likely
develops as a result of the ineffective transvascular and perivascular
clearance of Aβ[11,96],aswellaspoorAβclearance by arterial VSMCs
[62]. It was recently reported that microvascular rather than parenchy-
mal Aβdeposits are associated with early behavioral decits in
AD transgenic mice [97]. Individuals with CAA carrying APOE4
allele(s) have accelerated vascular pathology that can modulate Aβac-
cumulation [31]. Human post-mortem studies recently reported that
AD patients that are APOE4 carriers had increased brinogen deposits
with increased CAA disease severity compared to non-carriers, and the
brinogen deposits associated with microvascular Aβaccumulation
[31].
3.5.2. Basement membrane abnormalities
The basement membrane of the vessel wall has been shown to
thicken, split, and develop abnormal inclusions (e.g., accumulation of
collagen and perlecans) in the aging brain that is increased in AD as
shown by post-mortem human brain tissue studies [1,98].
3.5.3. String vessels
String vessels are thin connective tissue strands composed of base-
ment membrane that are remnants of capillaries without endothelial
cells or blood ow [99]. The number of string vessels is signicantly in-
creased in AD post-mortem brain tissue [99,100] and in APOE4 carriers
comparedto non-carriers [100]. Preliminary studies found that Aβaccu-
mulates substantially along string vessels [101].
4. Vascular risk factors, lifestyle, and environment
In addition to genetic risk factors discussed above that can trigger
neurovascular damage and cognitive decline, vascular conditions such
as hypertension, diabetes, atherosclerosis, and hyperhomocysteinemia
can also contribute to dementia and inuence one's risk for AD. Addition-
ally, every person is differentially affected by lifestyle (e.g., education,
sleep, diet, and exercise) and environment (e.g., pollution/nanopar-
ticles and environmental enrichment) that can further modify one's
risk for dementia. It is estimated that nearly half of AD cases might be
attributed to modiable risk factors and that effective control of
vascular factors, pre-existing disease(s), and psychological condi-
tion(s), as well as lifestyle-based interventions may offer promising
preventative strategies to delay disease onset and/or progression
[102]. Below, we detail some of these factors related to AD.
4.1. Hypertension
Hypertension is one of the vascular risk factors for dementia. Several
epidemiological studies indicate association of midlife hypertension
with late-life dementia [103,104]. A meta-analysis of six longitudinal
studies showed signicant association of hypertension with increased
risk and incidence of vascular dementia [105]. Hypertension causes
regional CBF reduction and impairs cerebrovascular reactivity [54].
Compelling evidence suggests that chronic hypertension fuels athero-
sclerosis in cerebral arteries and also increases the risk of microvascular
damage, white matter lesions, ischemic stroke, and intracranial hemor-
rhage in thepresence of CAA [106108]. In animal models,hypertension
caused BBB impairment, induced brain Aβaccumulation, enhanced Aβ-
induced neurovascular dysfunction and neurodegeneration [109112].
Circulating plasma levels of markers of endothelial activation including
soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular
cell adhesion molecule-1 (sVCAM-1), and endothelin-1 (ET-1), an
endothelial cell-derived potent vasoconstrictor, are increased in
hypertensive subjects suggesting vascular injury [107,113,114]. Anti-
hypertensive agents have been shown to reduce the risk of dementia
and cognitive decline [115,116], thus proper management of hyperten-
sion is an important protective strategy against cognitive impairment.
4.2. Diabetes
Increasing evidence suggests that type 2 diabetes mellitus (T2DM) is
a major vascular risk factor contributing to the development of AD
[117119]. Evidence of vascular alterations and increased BBB perme-
ability have been reported in T2DM patients [120,121] and in several
experimental models of diabetes [122125]. Multiple mechanisms
may explain the link between T2DM and pathological changes in brain
microvasculature, neurons, and glial cells including increased levels of
advanced glycation end-products (AGEs) and RAGE,vascular inamma-
tion, oxidative stress, reduced insulintransport across the BBB, impaired
insulin signaling, insulin resistance, and endoplasmic reticulum stress
[126,127].
4.3. Atherosclerosis
Atherosclerosis is hardening and narrowing of the inner wall of ar-
teries dueto the buildup of plaques composed of fatty deposits, choles-
terol, and other blood-derived substances. Atherosclerosis has been
implicated in the pathogenesis of dementia and AD, and it has several
overlapping risk factors including diabetes, hypercholesterolemia, and
aging [128]. Recently, a large cohort autopsy found that 77% of 410 AD
subjects had grossly apparent circle of Willis atherosclerosis, which oc-
curred more often than in non-AD subjects [129]. In non-demented pa-
tients, the carotid intima-media thickness, a marker of atherosclerosis,
was found to be inversely related to annual cognitive measures of exec-
utive function [130]. A large population-based study of 4371 stoke-free
middle-aged patients found that atherosclerosis could predict future
lower cognitive scores after 7 years [131]. Furthermore, a longitudinal
study of 1651 participants found that intima-media thickness was
associated with a higher risk of developing cognitive impairment in a
10 year follow-up study [132].
4.4. Hyperhomocysteinemia
Elevated plasma homocysteine, known as hyperhomocysteinemia,
has been reported in subjects with atherosclerosis [133], stroke [134],
cerebral small vessel disease [135,136],andAD[134,136].Cerebrovas-
cular damage, endothelial dysfunction, oxidative stress, demethylation,
and thrombosis have been proposed to elucidate the link between
6A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
hyperhomocysteinemia and AD [135,137,138]. Diet-induced hyperho-
mocysteinemia in wild-type [139] and APP/PS1 AD [140] mice leads to
spatial memory decits, microhemorrhages, neuroinammation, and
increased activity of MMP-2 and MMP-9.
4.5. Traumatic brain injury
Traumatic brain injury (TBI) increases the production of Aβand also
heightens the risk of developing AD [141]. Like AD, TBI leads to BBB
leakage and vascular breakdown involving NVU impairment [141].
Experimental studies in rats have demonstrated that TBI leads to focal
microbleeds, BBB, and endothelial damage, gliosis, macrophage-
mediated inammation, and myelin loss [142].
4.6. Sleep
Sleep inadequacy and daytime sleepiness increase the risk of AD and
development of Aβpathology [143]. Sleepwake cycle alterations in AD
subjects contribute to sundowning syndrome,when AD patients be-
come agitated, confused, anxious, and aggressive in the late afternoon
and evening. Patterns of sleep are also affected; for instance, rapid eye
movement sleep duration is reduced in AD, but not in normal aging,
and has been proposed to be a biomarker for AD [144]. Recent studies
found an increased clearance rate of Aβin sleeping mice compared to
awake mice following intracerebral injection of
125
I-Aβ40 into the
frontal cortex [145]. This increased Aβclearance was mediated 40% by
perivascular ISF-to-CSF bulk ow and the remaining 60% was likely
due to increased transvascular transport across the BBB [86,145].
Not only is sleep impaired in AD, but it has also been proposed that
disturbances in sleep can lead to AD. There is mounting evidence that
obstructive sleep apnea (OSA) could contribute to AD [146].Severe
OSA leads to sleep fragmentation, intermittent hypoxia, oxidative stress,
and increased production of Aβvia hypoxia-inducible factor-1αand β-
secretase 1 [146]. Following intermittent hypoxia, reoxygenation results
in damage to blood vessels and endothelial cells, and oxidative stress
[146]. Furthermore, mice undergoing chronic sleep restriction have
decreased expression and function of GLUT1, impaired tight junction
expression and BBB transport, and suppressed vascular reactivity
with reduced inducible nitric oxide synthase (iNOS), endothelial NOS
(eNOS), and ET-1 [147]. Also, rats subjected to sleep deprivation exhib-
ited BBB breakdown and leakage [148].
4.7. Pollution/nanoparticles
Air pollution has been shown to increase the risk of AD and AD-like
brain pathologies [149,150]. Young residents of the Mexico City Metro-
politan Area (MCMA) exposed to air pollution display cognitive impair-
ment, BBB disruption, Aβ42 plaques, and hyperphosphorylated tau
accumulation [151], which are exacerbated in APOE4 carriers [152].Fur-
thermore, children from the MCMA have increased serum autoanti-
bodies against neuronal proteins, likely due to compromised brain
immunity and BBB breakdown [153]. In mouse experimental studies,
aerosolized nickel nanoparticles caused a rapid and drastic increase in
Aβ40 and Aβ42 [154]. Also, APOE null mice exposed to mixed vehicle
exhaust have accelerated BBB breakdown, decreased expression of
tight junction proteins (e.g., occludin, claudin-5) and increased genera-
tion of reactive oxygen species activity [155].
Many types of nanomaterials are emerging in medical science and
research for their potential as biosensors, biomaterials, tissue engineer-
ing, DNA modication, or drug delivery [156]. The sources of nanoparti-
cles that humans are exposed to are numerous and include nanoscaled
debris from hip replacements, prostheses, cosmetics, sunscreen, and
many others. Unfortunately, nanoparticles have proven to be toxic in a
number of host systems [156]. Highly active nanoparticles (e.g., silica
coated to be hydrophilic, hydrophobic, or amphiphilic) can be taken
up by cellular membranes, including the BBB, and cross the membrane
passively or by carrier-mediated endocytosis [156]. Experimental stud-
ies in rodents have shown that silver, copper, or aluminum/aluminum
oxide nanoparticles disrupt the BBB, reduce the expression of endo-
thelial tight junctions, decrease CBF, and induce edema, synaptic
dysfunction, and neurodegeneration [157160]. Interestingly, silver
and copper nanoparticle exposureexacerbatedBBBdysfunction
when accompanying sleep deprivation [148] or diabetes [158].
4.8. Peripheral inammation
Peripheral inammation is being considered a possible risk factor for
AD [161] and dementia [162]. Infectious agents including pneumonia,
B. burgdorferi,Helicobacter pylori, and herpes simplex virus 1 (HSV-1)
have been identied in AD post-mortem brain tissue [163]. Interesting-
ly, HSV-1 infections are found more often in APOE4 carriers [164], which
have increased BBB permeability [30]. Additionally, dementia patients
have a two-fold increased mortality rate from pneumonia [165],and
pneumonia patients have elevated MMP-9 levels in their serum [166],
which is known to be linked to BBB breakdown [29]. Furthermore,
poor oral hygiene, oral inammation, and tooth loss worsen with age
and are risk factors for AD [167]. Recently, fungus was identied in
post-mortem brain tissue from AD subjects [168] and was found to lo-
calize around blood vessels in AD brain tissue [169]. In AD, infectious
agents likely enter the brain through a leaky, disrupted BBB and cause
more detrimental effects than they would normally if the BBB were
intact.
4.9. Alcohol and substance abuse
Alcoholabuse increases CBF and blood pressure and disrupts the BBB
causing vascular remodeling by oxidative stress, endothelial tight junc-
tion phosphorylation, and changes in expression of BBB-degrading
gelatinases MMP-2 and MMP-9 [170,171]. Likewise, drug abuse has
been shown to have detrimental effects on the BBB. Psychostimulant
drugs of abuse including methamphetamine, ecstasy/MDMA (3,4-
methylenedioxymethamphetamine), cocaine, and nicotine cause in-
creased BBB permeability through alterations in tight junction protein
expression and conformation, glial activation, enzymeactivation related
to BBB cytoskeletal remodeling, and induction of neuroinammation
[172174]. In addition to increased BBB permeability, experimental
studies have found that even a single acute exposure to methamphet-
amine causes profound CBF reductions [175]. Also, recent preliminary
studies have found that heroin use leads to microvascular damage
and microcirculation dysfunction, collapse, and fracture of the mye-
lin sheath and vacuole formation in white matter regions around
microvessels, as identied in post-mortem human brain tissue
[176,177].
5. Vasculoprotective approaches
With the substantial amount of evidence supporting the vascular
link to AD and related dementias, using approaches to repair
neurovascular damage is intuitive and may hold promise to delay and/
or slow down cognitive decline. Likely, the best approach for treatment
will be multi-targeted and potentially individualized, patient-specic,
since AD, CAA, and vascular dementia present complex and heteroge-
neous etiologies. Below, we focus on some approaches that could poten-
tially restore neurovascular functions and/or protect the neurovascular
system from pathophysiological changes seen in dementia and AD.
5.1. Restoring BBB Aβtransport machinery
5.1.1. LRP1 upregulation
LRP1 expression in cerebral vessels is reduced in AD [11,84],and
therefore increasing microvascular LRP1 expression levels may increase
Aβclearance to thereby prevent development of Aβ-dependent
7A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
pathologies. Future studies should investigate novel therapeutic drugs
and/or gene therapy vectors to restore LRP1 levels in endothelial cells
and pericytes at the BBB. In addition to increasing LRP1 on cerebral
microvessels, restoration or selective enhancement of LRP1 by gene
therapy in the liver could function as a systemic vacuumto increase
the concentration gradient driving Aβout of the brain by creating a pe-
ripheral sink[87]. In general, gene therapy targeting neurological dis-
orders remains challenging due to the restricted entry of vectors across
the BBB into the brain. However, targeting cell surface (e.g., GLUT1,
LRP1) or cytoplasmic (e.g., PICALM) proteins whose expression is re-
duced in AD brain endothelium (Fig. 3B) would likely be more achiev-
able due to the favorable anatomical position, as endothelial cells are
directly accessible to therapeutic interventions by intravenous adminis-
tration.Importantly, studies have used in vivo phagepanning to identify
modiable epitopes on adeno-associated virus type 2 (AAV2) vectors to
enable endothelial-specic gene therapy delivery [178,179].
Soluble L RP1 and/or its wild-type recombinant cluster IV, WT-LRPIV,
bind to free Aβaiding in its peripheral clearance and preventing it from
reentering the brain via the RAGE receptor [180].Recently,amutantof
LRPIV (LRPIV-D3674) was developed to preferentially and selectively
bind neurotoxic Aβcompared to other LRP1 ligands [181].LRPIV-
D3674 is ~25% more effective at replacing oxidized sLRP1 and clearing
endogenous Aβin hippocampus and cortex in AD transgenic mice
[181]. Therefore, LRPIV-D3674 has a therapeutic potential in AD to
restore reduced or oxidized sLRP1, regulate peripheral Aβlevels, and
reestablish the Aβhomeostatic peripheral sink[180].
5.1.2. PICALM upregulation
As described above, PICALM critically regulates transcytosis and
clearance of Aβacross the BBB and its levels are reduced in AD brain en-
dothelium, as well as in individuals carrying non-protective PICALM
alleles [41]. To date, there are no known drugs or gene therapy vectors
that can increase PICALM expression levels. Future studies are needed
to determine the benet of increasing PICALM levels in AD models
and AD.
5.1.3. GLUT1 upregulation
GLUT1 levels at the BBB correlate with brain glucose uptake [82,182]
and also are critical for maintaining BBB integrity [79].Importantly,the
levels of GLUT1 in cerebral microvessels are reduced in AD [78,183].
Only a few studies have investigated drugs to upregulate GLUT1 expres-
sion. For example, one study found that ginsenoside Rb1, an active com-
ponent of ginseng, can activate the insulin signaling and AKT pathways
to increase expression of GLUT1 and GLUT4 in adipocytes of diabetic
(db/db) mice [184]. Studies in rats found that cerebrolysin, an approved
neurotrophic peptide for vascular dementia treatment in humans, in-
creased GLUT1 expression and improved hippocampal learning and
memory [185]. Although these few studies demonstrate increased
GLUT1 expression, themolecular mechanisms underlying GLUT1 reduc-
tions in AD remain unknown. Furthermore, it is not known whether
manipulating GLUT1 expression at the BBB in dementia and in AD pa-
tients will have an effect on BBB permeability, cognitive performance,
and Aβpathology as shown in an animal model of AD and GLUT1 de-
ciency [79].
5.1.4. Blocking RAGE
Two highly specic, low-molecular-weight, high-afnity RAGE
inhibitors, FPS2 and FPS-ZM1, have been recently reported [91].
FPS-ZM1, a novel multimodal RAGE blocker that crosses the BBB,
reduced inux of Aβinto the brain, improved CBF responses, downreg-
ulated β-secretase activity, decreased amyloid load, suppressed
neuroinammatory responses, and reduced behavioral decits in a
mouse model of AD [91]. Similarly, in a rodent model of hypertension,
RAGE inhibition by FPS-ZM1 signicantly reduced hypertension-
induced AD pathology as shown by improved cognitive performance
and reduced parenchymal Aβdeposition [110]. RAGE inhibitors are
currently being examined in Phase 3 clinical trials for efcacy in mild
to moderate AD (NCT02080364) [186,187]. See Fig. 3B.
5.2. Microvascular stabilization
5.2.1. Activated protein C (APC)
APC is a vasculoprotective protease that promotes cytoprotective
signaling in injured and ischemic brain endothelium at the BBB [188,
189]. APC also stimulates post-ischemic brain angiogenesis, vascular re-
pair, and neurogenesis [188191]. In the CNS endothelium, APC acti-
vates protease-activated receptor-1 (PAR-1), which elicits protective
signaling by enhancing the BBB integrity via Rac1-dependent cytoskel-
etal stabilization, suppression of cerebrovascular MMP-9 activity, and
inhibition of proinammatory cytokines expression and apoptosis
[188,189,192194]. A genetically engineered variant of APC, 3K3A-
APC, with normal cell signaling and greatly reduced anticoagulant activ-
ity has an excellent safety prole in primates and humans [195,196] and
is currently being studied as a neuroprotective agent in a Phase2a clin-
ical trial for ischemic stroke(NCT02222714). APC therapy holds poten-
tial to protect and restore cerebrovascular function and BBB breakdown
in various other neurological disorders, as shown in different experi-
mental models, and might have also applications in dementia and AD.
5.2.2. CypA and MMP-9 inhibitors
The detrimental effects of APOE4 on BBB and NVU function are
mechanistically linked to the CypA-NFκB-MMP-9 proinammatory
pathway [29,35]. There are several new CypA inhibitors recently
developed and investigated for use against hepatitis-C and HIV
infections including CPI-431-32 [197], compound 25 [198], SCY-635
[199], and MM284 [200], which all may have a potential to stabilize
the BBB in APOE4 carriers. In addition to CypA inhibitors, there are a
number of identied MMP-9 inhibitors including minocycline [201],
curcumin [202], SB-3CT(2) [203], and compound 18 [204].Forexample,
minocycline has been demonstrated to reduce hemorrhage frequency
and increase endothelial tight junction and basement membrane pro-
teins in aged 5xFAD/APOE4 transgenic mice [201]. Furthermore, recent
studies showed that minocycline signicantly reduced the infarct size,
prevented tissue loss, improved perfusion, reduced BBB permeability,
and increased tight junction protein levels in spontaneously hyperten-
sive stroke-prone rats [205,206]. Future studies should determine the
benet of CypA and MMP-9 inhibitors on vascular dysfunction in AD
and APOE transgenic mouse models.
5.2.3. Anti-hypertensive drugs
Many studies in experimental animal models and clinical studies
show that pharmacological intervention by angiotensin receptor
blocker, angiotensin converting enzyme inhibitor, or RAGE inhibitor is
effective in treating hypertension-related vascular injury [207209],re-
ducing AD-related pathological changes in brain [209,210], and slowing
cognitive decline [209,211]. Furthermore, developing future therapies
capable of lowering expression of VCAM-1, ICAM-1, and/or blocking
ET-1 receptor hold promise to further reduce hypertension-induced
cerebrovascular dysfunction.
5.2.4. Fibrinogen depletion
Ancrod is a drug derived from the Malayan pit viper that contains
a serine protease that cleaves brinopeptide A (FPA), essentially
preventing conversion of brinogen to brin that results in brinogen
depletion [212]. The potentially benecial mechanism of Ancrod is its
ability to lessen brinogen clot propagation and improve CBF via activa-
tion of endogenous brinolysis [212]. Studies in TgK21p55
+/
mice, a
MS model that exhibits clinical symptoms of paralysis and BBB break-
down, found that Ancrod treatment delayed the onset of inammatory
demyelination by diminishing brinogen deposition [213]. Additionally,
clinical trials of Ancrod in ischemic stroke have yielded different results
depending on time of treatment; for instance, Ancrod was clinically
8A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
benecial when administered within 3 h post-stroke [214] but exhibit-
ed no benet when administered within 6 h post-stroke [215]. Ancrod's
mechanism was recently studied in vitro in cultured human endothelial
cells grown in ischemic conditions and in stroke subjects. In both cases,
Ancrod decreased brinogen levels and increased FPA levels and re-
duced clot formation [212].
5.3. Lifestyle improvements for vascular health
5.3.1. Diet
Recent studies report that diet can mediate the vasculoplastic
reserve of the hippocampus. For example, consuming high levels of
cocoa avanols increased capillary density and enhanced dentate
gyrus-associated cognitive function in cognitively normal healthy sub-
jects [216]. This suggests an interaction between vasculoplasticity and
neuronal plasticity during normal aging and dementia, but how this re-
lationship is affected by lifestyle and vascular risk factors is currently
unclear and should be investigated in future studies [13].
Growing evidence supports the benets of a Mediterranean diet in
protecting against dementia and prolonging one's cognitive reserve
during aging. Age-related cognitive decline was attenuated in individ-
uals consuming a Mediterranean diet, as found in a recent study of the
Mediterranean-Dietary Approach to Systolic Hypertension (DASH)
diet intervention for neurodegenerative delay (MIND) [217].Incompar-
ing Mediterranean and Western diets, the primary difference is the
source and proportion of dietary fats, with olive oil specically being
the main fat consumed in the Mediterranean diet and high levels of
saturated fatty acids and simple carbohydrates being consumed in
Western diets [218]. Microvascular dysfunction is evident in rodent
models fed unhealthy diets, namely, those fed diets of Western cul-
ture [219],highfat[220], and high cholesterol [221]. An intact BBB
is needed for proper cholesterol metabolism [222]. In CSF, decreased
cholesterol levels correlate with decreased Aβ42 and increased CSF
APPαand APPβ(products of APP processing) levels, supporting an
association between disrupted cholesterol metabolism and in-
creased amyloidogenesis [223].
Resveratrol is a biologically active plant-derived phytoalexin. Res-
veratrol has been shown to cross BBB and regulate expression of
MMPs, reduce pericyte loss, maintain integrity of BBB, and promote
Aβclearance [224226]. Treatment with resveratrol completely re-
versed diabetes-induced vascular dysfunction by reducing capillary
leakage,pericyte degeneration, and VEGF protein expression in the mu-
rine retina [227]. An earlier study has shown that resveratrol inhibits
RAGE expression in vascular cells [228], which is implicated in Aβtrans-
port into the brain and accelerated Aβpathology in a mouse model [91].
Furthermore, long-term consumption of resveratrol reduced oxidative
stress and prevented behavioral decits in a rat model with disrupted
NVU [229].
Olive oil is high in essential omega-3 fatty acids, the major com-
ponent of which is docosahexaenoic acid (DHA), and has long been
reported to benet cognition and overall brain health [230].DHA
cannot be synthesized by the body and thus must be consumed,
and the primary transporter of DHA from blood-to-brain is the
major facilitator superfamily domain containing 2A (MFSD2A) at
the BBB [231]. Individuals with AD have lower CSF DHA lipid levels,
and those with mild dementia have lower CSF α-liolenic acid levels
[232]. Interestingly, reduced MFSD2A expression at the BBB can
lead to a loss of its important functions, including maintenance of
BBB integrity and omega-3 fatty acid transport into the brain [231,
233,234].Ofnote,transgenicAPOE4 mice also exhibit reduced up-
take of DHA into the brain compared with transgenic APOE2 mice
[235],butwhetherthisisrelatedtoreducedMfsd2a expression is
currently unknown. Additional studies are needed elucidate the un-
derlying mechanisms of MFSD2A and fatty acids in relation to de-
mentia and AD.
5.3.2. Exercise and environmental enrichment
Regular exercise and physical activity, particularly during midlife,
are associated with improved cerebrovascular function and reduced
rates of dementia and AD [236]. Individuals that exercised regularly
for 28 days exhibited reduced plasma homocysteine levels and in-
creased endothelial progenitor cells in peripheral blood, factors
that protect against vascular damage and cognitive impairment
[237]. Experimental studies in diabetic rats have shown that tread-
mill exercise maintains claudin-5 expression at the BBB compared
to rats not receiving exercise [238]. Mechanistically, physical activity
and cognitive stimulation in the form of enriched environment
(e.g., tunnels, balls, ladders, and running wheel) accelerated Aβen-
zymatic degradation and enhanced transvascular Aβclearance, re-
ducing Aβaccumulation in brains of AD transgenic mouse models
[239,240]. Additionally, physical activity promoted Aβclearance
from brain to blood via upregul ation of LRP1 [241,242] and downreg-
ulation of RAGE [91] at the BBB. Mice without access to a running
wheel had decreased occludin tight junction levels and disrupted
BBB integrity [243]. Although recent attention has been given to ex-
ercise, additional studies are needed to more completely understand
the mechanism underlying its benecial effects.
6. Conclusions and critical questions
Here, we have described the compelling evidence supporting the
neurovascular link to cognitive impairment, dementia, and AD. Speci-
cally, how cerebrovascular functions in humans and animal models are
affected and/or altered by genetic risk factors for AD and modiable
vascular risk factors, lifestyle, and environment, which in turn can all
inuence development of dementia and AD.
The exact role of the vascular system in the pathophysiogenesis of
dementia and AD and whether the vascular system is a viable therapeu-
tic targetfor dementia and AD still remain,however, to be better under-
stood and/or dened by future studies. Some critical questions that
perhaps need to be addressed by studies in humans are, for example:
i) Do cerebrovascular changes drive the initial pathogenic events in
the living human brain leading to neuronal injury, disrupted structural
and functional brain connectivity, and early cognitive declinein sporad-
ic AD and/or individuals with genetic risk for AD (i.e., APOE4) or ADAD
(i.e., PSEN1) compared to those at a lower risk? ii) Do cerebrovascular
changes lead to cognitive decline in individuals with vascular risk fac-
tors such as diabetes or hypertension? iii) Do reductions in the resting
CBF and/or CBF dysregulation and BBB breakdown precede changes in
structural and functional brain connectivity in the living human brain,
and can these cerebrovascular abnormalities be detected early in the
disease process in AD and ADAD patients and/or in individuals with
vascular risk factors?
In parallel to addressing these translational questions, there is an
emerging need for novel molecular and imaging biomarkers to pre-
dict cognitive decline, dementia, and AD, including development of
biomarkers for neurovascular dysfunction, and to determine wheth-
er these biomarkers can serve as reliable new diagnostic and/or
prognostic tools for predicting cognitive impairment and the decline
to dementia. From the experimental preclinical laboratory side, it
would be extremely interesting to evaluate whether genetic, vascu-
lar, and/or mechanical manipulation of the cerebrovascular system
to advance vascular/BBB injury functions inuence the course of
neurological disorders and AD-like pathology in animal models of
dementia and AD, as it does in som e models of human rare mono gen-
ic diseases [83,244246].
Finally, new experimental studies should reveal whether therapeu-
tic targeting of cerebrovascular dysfunction, including BBB breakdown
and dysregulated CBF, could inuence the course of disease in experi-
mental models of AD, and importantly, could these ndings then be
translated to humans affected by dementia and AD.
9A.R. Nelson et al. / Biochimica et Biophysica Acta xxx (2015) xxxxxx
Please cite this article as: A.R. Nelson, et al., Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease, Biochim.
Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.12.016
Transparency Document
The Transparency document associated with this article can be
found, in online version.
Acknowledgments
The work of B.V.Z. is supported by the National Institutes of
Health grants R01AG023084, R01NS090904, R01NS034467, and
R01AG039452 and the Cure for Alzheimer's Fund (006002-00001).
We apologize to those authors whose original work we were not
able to cite due to the limited length of this review.
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