REVIEW Open Access
Neurovascular dysfunction, inflammation and
endothelial activation: Implications for the
pathogenesis of Alzheimer’s disease
Alzheimer’s disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia.
Alzheimer’s disease is an increasingly prevalent disease with 5.3 million people in the United States currently
affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8
million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of
Alzheimer’s and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each
year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain
elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only
modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on
disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects
are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has
focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing
literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic
cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic
inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative
diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular
abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the
endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally
altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.
Alzheimer’s disease (AD) is an age-related disorder
characterized by progressive cognitive decline and
dementia. Alzheimer’s disease is an increasingly preva-
lent disease with 5.3 million people in the United States
currently affected; it is the sixth-leading cause of death.
The direct and indirect costs of Alzheimer’s and other
dementias to Medicare, Medicaid and businesses
amount to more than $172 billion each year . Despite
intense research efforts, effective disease-modifying
therapies for this devastating disease remain elusive.
The clinical entity AD has, by definition, been categor-
ized as a “non-vascular” dementia. Widely used diagnostic
criteria classify dementia as either vascular or AD-dri-
ven; despite the reality of clinical practice where vascu-
lar comorbidity may be present in 30%-60% of AD
patients and, conversely, AD pathology may be present
in 40%-80% of vascular dementia patients . Because
of its classification as a non-vascular dementia, the
role of neuro-vascular interactions in the evolution of
neuronal injury in AD brain has been underappre-
ciated. Nevertheless, increasing literature supports a
vascular-neuronal axis in AD as shared risk factors for
both AD and atherosclerotic cardiovascular disease
implicate vascular mechanisms in the development
and/or progression of AD.
Cardiovascular risk factors in AD
Numerous studies link vascular risk factors to cognitive
decline and dementia in the elderly [3-32]. Old age,
Garrison Institute on Aging, and Department of Neurology, Texas Tech
University Health Sciences Center, Lubbock, Texas, USA
Grammas Journal of Neuroinflammation 2011, 8:26
© 2011 Grammas; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
atherosclerosis, stroke, hypertension, transient ischemic
attacks, cardiac disease, the epsilon 4 allele of the apoli-
poprotein E (ApoE), elevated homocysteine levels,
hyperlipidemia, metabolic syndrome, obesity and dia-
betes are risk factors for both vascular dementia and
AD [5-7,10-16]. Homocysteine, considered an indepen-
dent risk factor for vascular disease, has also been
shown to increase the risk of AD [7,16]. Several studies
have shown a high correlation between cardiovascular
mortality and AD and an association among hyperten-
sion, diabetes and dementia [21,23-28]. Inheritance of
the ApoE allele ε4 increases the risk of developing both
atherosclerosis and late-onset AD, suggesting a vascular
component to the pathogenesis of neuronal degenera-
tion in AD . There is increasing evidence identifying
a link between heart disease and AD [2,8-15,17,19,20].
Heart disease is a prevalent finding in AD, and may be a
forerunner to the dementing disorder. Also, increased
prevalence of AD-like amyloid beta (Ab) deposits in the
neuropil and within neurons occurs in the brains of
non-demented individuals with heart disease [3,4].
There is a three-fold increase in risk of developing AD
or vascular dementia in people with severe atherosclero-
sis . The large population-based Rotterdam study
finds that atherosclerosis, primarily in the carotid
arteries, is positively associated with the risk of develop-
ing dementia . Postmortem grading of Circle of
Willis atherosclerotic lesions shows that atherosclerosis
is more severe in cases with AD and vascular dementia
than in non-demented controls . Finally, the idea
that vascular dysfunction is a primary/central event in
the pathogenesis of AD has been proposed in the con-
text of a two-hit model of AD pathogenesis [19,32].
This hypothesis postulates that neurovascular damage is
a primary occurrence and that subsequent injuries
including Ab deposition amplify and/or exacerbate vas-
cular damage which then leads to neurodegenerative
processes/events and ultimately cognitive decline.
Functional and structural cerebrovascular
abnormalities in AD
Abnormalities in the vascular system of the brain could
contribute to the onset and/or progression of neurode-
generative events in AD . Elevated levels of markers
of endothelial dysfunction (E-selectin, vascular cell adhe-
sion molecule 1(VCAM-1)) have been determined in the
plasma of older subjects with late onset AD and vascular
dementia . Data from brain imaging studies in
humans and animal models suggest that cerebrovascular
dysfunction precedes cognitive decline and the onset of
neurodegenerative changes in AD and AD animal mod-
els [35,36]. Emission tomography including single
photon emission computed tomography (SPECT) and
positron emission tomography (PET) show AD is char-
acterized by bilateral temporoparietal hypoperfusion on
SPECT and hypometabolism on PET which precede
onset of dementia . The Alzheimer’s Disease Neuroi-
maging Initiative (ADNI) has examined longitudinal
change in glucose metabolism using [(18)F]-fluorodeox-
yglucose PET (FDG-PET) and finds the use of FDG-
PET as an outcome measure in clinical trials increases
statistical power over traditional cognitive measure-
ments, aids in subject selection, and reduces clinical
trial sample size .
The idea that vascular defects are present in AD and
may be important in disease pathogenesis was suggested
over 25 years ago . The two-hit hypothesis of AD
pathogenesis emphasizes the primary role of vascular
defects and data linking brain endothelial cell products
with neuronal cell death in AD, further support a central
role for vascular abnormalities in disease pathogenesis
[19,32,33]. Numerous structural and functional cerebro-
microvascular abnormalities in AD have been identified
[40-56]. These are atrophy and irregularities of arterioles
and capillaries, swelling and increased number of pinocy-
totic vesicles in endothelial cells, increase in collagen IV,
heparin sulfate proteolglycans and laminin deposition in
the basement membrane, disruption of the basement
membrane, reduced total microvascular density and occa-
sional swelling of astrocytic end feet [39,41,42,45,48,56].
Ultrastructural analysis of the blood-brain barrier in AD
patients demonstrates decreased mitochondrial content,
increased pinocytosis, accumulation of collagen and focal
necrotic changes [48,50,56]. Structural changes in cere-
bral capillaries in elderly patients correlate positively with
advanced age and dementia . Also, vascular distor-
tions such as vessel kinking, twisting, tortuosity, and
looping occur in AD . Neuronal cell loss in AD may
result from pathologic changes in vessel angioarchitec-
ture, decreased cerebral blood flow, and altered oxygen
utilization leading to cerebral microcirculatory impair-
ment. Microvascular pathology displays regional and
laminar patterns that parallel patterns of neuronal loss
. There is a topographic association of capillaries with
neuritic plaques [40,43]. In addition, vascular-derived
heparin sulfate proteolglycan deposits co-localize with
senile plaques . A study using vascular corrosion
casts to visualize the 3D arrangement of the brain vascu-
lature, shows that in young AD animals, lacking parench-
abnormalities of blood vessels are evident . Reduced
staining of endothelial markers CD34 and CD31 observed
in AD brains suggests that there is an extensive degen-
eration of the endothelium during the disease progression
. Taken together, these data suggest profound vascu-
lar perturbations in AD.
Grammas Journal of Neuroinflammation 2011, 8:26
Page 2 of 12
Neuroinflammation, vascular inflammation and the
pathogenesis of AD
Data suggest that there are important pathogenic
mechanisms common to both Alzheimer’s and cardio-
vascular disease. Chronic inflammation, characterized by
elevated plasma concentrations of C reactive protein, a
plasma acute-phase protein, is associated with an
increased risk of atherosclerosis and has been documen-
ted in the lesions of AD [58-60]. Inflammation, by defi-
nition a vascularized tissue response to injury, is a key
connector linking vascular abnormalities and AD patho-
genesis. A wide range of inflammatory cytokines and
chemokines has been documented to play a role in the
evolution of the atherosclerotic plaque. Indeed, vascular
inflammation, especially of the endothelium, is central
to the initiation and progression of the atherosclerosis
[61,62]. Chronic inflammation is associated with a broad
spectrum of neurodegenerative diseases of aging includ-
ing AD . Numerous studies show the presence of
markers of inflammation in the AD brain [64-71]. Ele-
vated cytokines and chemokines as well as the accumu-
lation of activated microglia are found in or near the
pathologic lesions of AD [65,70]. In animal models of
AD lipopolysaccharide (LPS)-induced inflammation has
been shown to exacerbate phosphotau pathology .
Retrospective epidemiological studies suggest that a
wide variety of non-steroidal anti-inflammatory drugs
(NSAIDs) may significantly reduce one’s lifetime risk of
developing AD [73-76]. These drugs inhibit the enzy-
matic activity of cyclooxygenase-1 (COX-1) and inducible
COX-2 which catalyze the first committed step in the
synthesis of prostaglandins. Inducible COX-2 is elevated
in AD; both COX-1 and 2 are involved in numerous
inflammatory activities. COX inhibitors can decrease
levels of highly amyloidogenic Ab1-42 peptide .
Long-term use of NSAIDs is also associated with protec-
tion from the development of AD and reduction in Ab
deposition in mouse models of AD and is positively cor-
related with reduction of plaque-associated microglia in
both humans and mice [78-82]. A meta-analysis of epide-
miological data shows that NSAIDs reduce AD incidence
by an average of 58% . Despite considerable animal
and retrospective human studies that show beneficial
effects of anti-inflammatory drugs in mitigating AD
pathology, NSAIDs have failed to demonstrate therapeu-
tic benefit in prospective AD clinical trials [84-86]. No
detectable effects on a variety of clinical outcome mea-
sures of AD progression are found in controlled trials of
naproxen, celecoxib, and rofecoxib [84,86]. Results of a
clinical trial with more than 2500 participants show no
significant cognitive improvement after 4 years of treat-
ment with either naproxen or celecoxib . A large
phase III trial of fluriproen recently provided no evidence
of cognitive improvement in AD subjects .
Increasingly the timing of anti-inflammatory adminis-
tration appears critical. The Cache county study sug-
gests that NSAIDs help prevent cognitive decline in
older adults if started in midlife rather than late life
. In a study in AD transgenic mice, the reentry of
neurons into the cell cycle, a pathologic feature of AD,
is prevented but not reversed by NSAIDs, suggesting
that inflammation is important for initiation but not the
progression of the disease process . It is likely that
the neurodegeneration observed in AD is the result of
pathogenic processes including inflammation initiated
well before the onset of cognitive symptoms associated
with the disease. Recent findings suggest that alterations
in production of inflammatory cytokines and chemo-
kines are early features that precede Ab deposition in
mouse models of AD [88-90]. Early expression of
inflammatory mediators in the AD brain by non-neuro-
nal cells, including endothelial cells, is likely critical to
the development of disease.
In AD there is a robust elevation in inflammatory
mediators in the cerebral microcirculation. AD brain
endothelial cells express high levels of inflammatory
adhesion molecules such as monocyte chemoattractant
protein-1 (MCP-1) intercellular adhesion molecule-1
(ICAM-1) and cationic antimicrobial protein 37 kDa
(CAP37) [54,91,92]. Compared to microvessels from
age-matched controls, AD brain microvessels release
significantly higher levels of a number of inflammatory
factors including nitric oxide (NO), thrombin, tumor
necrosis factor-a (TNFa), transforming growth factor-b
(TGF-b), interleukin (IL) IL-1b, IL-6, IL-8, and matrix
metalloproteinases (MMPs) [46,54,55,93]. The cerebral
microvasculature is a participant in a destructive cycle
of events where inflammation precedes Ab deposition
and Ab in turn promotes release of inflammatory med-
iators. In this regard, exposure of brain endothelial cells
to Ab has been shown to evoke an array of pro-inflam-
matory responses. Ab, via its interaction with the recep-
tor for advanced glycation end products (RAGE) up-
regulates CCR5 expression and promotes T cell migra-
tion across the blood-brain barrier . Monocytes are
transported across the BBB via Ab-RAGE-mediated sig-
naling . Inhibitors of c-Jun NH2-terminal kinase
(JNK), extracellular signal-regulated protein kinase
(ERK), and phosphatidylinositol 3’-kinase (PI3K) signal-
ing cascades significantly decrease Ab-induced CCR5
expression in human brain endothelial cells . Cul-
tured brain endothelial cells exposed to Ab1-40 up-
regulate expression of inflammatory genes MCP-1, IL-1b,
and IL-6. Quantitative RT-PCR analysis confirms ele-
vated expression of these genes in AD and AD/CAA
brains . Treatment of isolated brain microvessels
with Ab results in an increase in prostaglandin produc-
tion . Cultured brain endothelial cells exposed to Ab
Grammas Journal of Neuroinflammation 2011, 8:26
Page 3 of 12
express CD40 and secrete interferon-gamma and IL-1b
. The cerebromicrocirculation is a dynamic interface
serving as both a source of, and a target for, inflamma-
Inflammation and angiogenesis: implications for AD
The mechanisms whereby inflammatory events and
mediators contribute to AD pathogenesis are unclear.
Specifically, the link between vascular inflammation and
neuronal dysfunction and death, pathognomonic
abnormalities in the AD brain, has not been defined. In
the periphery, chronic inflammation as a regulator of
angiogenesis has been documented [99,100]. The finding
that inflammation is often associated with increased
angiogenesis is explained by inflammation-induced pro-
duction of pro-angiogenic factors.
The possible linkage of inflammation and angiogenesis
in the brain has not been widely examined in AD. How-
ever, data are emerging to support the idea that factors
and processes characteristic of angiogenesis are found in
the AD brain. Genome-wide expression profiling in the
AD brain has identified a marked upregulation of genes
that promote angiogenesis . Cerebral hypoperfusion
is one of the major clinical features in AD and likely
plays a critical role in its pathogenesis . Hypoxia is
known to stimulate angiogenesis as well as contribute to
the clinical and pathological manifestations of AD
[102,103]. Hypoxia causes upregulation of hypoxia-indu-
cible genes such as vascular endothelial growth factor
(VEGF) [103,104]. VEGF, a potent mediator of angio-
genesis, is present in the AD brain in the walls of intra-
parenchymal vessels, diffuse perivascular deposits, and
in clusters of reactive astrocytes . In addition,
intrathecal levels of VEGF in AD are related to clinical
severity and to intrathecal levels of Ab . Increasing
evidence suggests that polymorphisms within the pro-
moter region of the VEGF gene may elevate the risk for
AD . Brain microvessels express and release a large
number of inflammatory proteins (1L-1b, IL-6, IL-8,
TNFa, TGFb, MCP-1); many of which have been impli-
cated in angiogenesis [54,55,93] In addition, the vascula-
ture demonstrates up-regulation of specific molecules
thought to be important regulators/markers of the
angiogenic process including thrombin, VEGF, angio-
poietin-2, integrins (aVb3aVb5), and hypoxia inducible
factor 1a (HIF-1a) [93,108,109]. The notion that inflam-
mation and angiogenesis are interrelated molecular
events is supported by studies showing that IL-1b, a
major proinflammatory cytokine, can substitute for key
aspects of hypoxia signaling, including induction of
VEGF gene expression [101,110]. This may be especially
relevant for AD pathophysiology as high levels of this
cytokine in AD- but not control-derived microvessels
have been reported . Taken together, these data
suggest a heretofore-unexplored connection between
angiogenesis and AD.
Despite increases in several pro-angiogenic factors in
the AD brain, evidence for increased vascularity in AD
is lacking. On the contrary, it has been suggested that
the angiogenic process is delayed and/or impaired in
aged tissues, with several studies showing decreased
microvascular density in the AD brain [111-113]. Work
from Mullan’s group has shown that wild-type Ab pep-
tides have antiangiogenic effects in vitro and in vivo
. Also, impaired angiogenesis has been demon-
strated in AD transgenic mice . Recent data show
that an amyloid peptide Ab1-40 (E22Q), derived from
individuals with the rare autosomal dominant disorder
hereditary cerebral hemorrhage with amyloidosis-Dutch
type, has stronger anti-angiogenic activity than wild-type
Ab peptides and is poorly cleared from the brain
[116,117]. This appears to be related to the increased
formation of low molecular weight Ab oligomers in the
culture medium surrounding human brain microvascu-
lar endothelial cells. The notion that amyloid may serve
as a “brake’” in the angiogenic process is also supported
by data which show that plaque-derived amyloid inhibits
brain endothelial cell proliferation in vitro . Recent
genomic profiling of brain endothelial cells shows low
levels of vascular-restricted mesenchyme homeobox 2
gene (MEOX2) in AD individuals lead to aberrant
angiogenesis and premature pruning of capillary net-
works resulting in reductions in the cerebral microcircu-
lation and that hypoxia suppresses MEOX2 expression
in brain endothelial cells . Furthermore, in that
study a transgenic mouse line deficient in MEOX2 gene
displays vascular regression and poor Ab clearance.
The angiogenic process is complex and involves sev-
eral discrete steps beginning with endothelial activation.
The activated endothelium synthesizes and secretes a
large number of pro-angiogenic mediators [120,121]. In
physiologic angiogenesis endothelial activation is reversi-
ble and self-limiting. We propose a working model to
reconcile the seemingly contradictory observations of
both a large number of pro-angiogenic mediators and
an absence of new vessel growth in the AD brain. In
response to a persistent or intermittent stimulus, such
as cerebral hypoperfusion, one of the major clinical fea-
tures of AD, brain endothelial cells become activated.
Activated endothelial cells are highly synthetic and
release a host of factors that can affect the activation of
nearby cells (i.e. astrocytes, microglia) and/or the viabi-
lity of neurons. Despite the continued presence of the
stimulus, no new vessel growth occurs. The inhibition
of vascular growth is likely mutlifactorial and could
involve the anti-angiogenic activity of Ab, defective
homeobox signaling, as well as combinations of these
and other mechanisms [115-119]. Because no new
Grammas Journal of Neuroinflammation 2011, 8:26
Page 4 of 12
vessels are formed, there are no feedback signals to shut
off vascular activation endothelial cells. In AD reversible
endothelial activation becomes irreversible endothelial
dysfunction. The vascular products of a permanently
dysfunctional endothelium could cause neuronal injury.
A diagram of this hypothesis is shown in Figure 1.
Results of epidemiological studies suggest that some
drugs purported to have beneficial effects in AD inhibit
angiogenesis [122-125]. The idea that vascular inflam-
matory changes that promote angiogenesis have func-
tional consequences in AD is supported by data
suggesting that some of the beneficial effects of NSAIDs
are linked to anti-angiogenic activity [126-128]. NSAIDs
might inhibit angiogenesis through several mechanisms.
These drugs can directly inhibit angiogenic signaling
pathways such as mitogen-activated ERK2 in endothelial
cells . NSAIDs can also inhibit endothelial growth
factor expression and subsequent migration . Also,
the enzymes COX-1 and COX-2, targets of NSAIDs, are
important regulators of angiogenesis . The efficacy
of COX-2 selective inhibitors in AD treatment may be
related to the inhibition of prostaglandins, NO and
TNFa, all of which are important to both inflammation
and angiogenesis . Thalidomide, another anti-
angiogenic drug which blocks endothelial cell activation
and suppresses release of VEGF and TNFa, appears pro-
tective in animal models of AD preventing memory
impairment induced by Ab [132,133]. Also, statins, pur-
ported to have beneficial effects in AD, have anti-
angiogenic effects [134-136].
Endothelial cell activation and neuronal injury
Endothelial cells are key modulators of inflammation
and angiogenesis . The endothelium is a common
target for all cardiovascular risk factors, and functional
impairment of the vascular endothelium in response to
injury occurs long before the development of overt dis-
ease [137-139]. Chronic inflammation is tightly linked to
diseases associated with endothelial dysfunction. Pheno-
typic modulation of endothelium to a dysfunctional
state is recognized to contribute to the pathogenesis of
cardiovascular diseases such as atherosclerosis [140,141].
Endothelial dysfunction is also increasingly implicated in
the development of neurodegenerative diseases such as
AD [19,32,33,142-146]. Brain endothelial cells regulate
the neuronal milieu both by their synthetic functions as
well as by their blood-brain barrier function. Therefore,
disturbance in cerebrovascular metabolic or transport
Figure 1 Diagram of hypothesis. In response to a persistent or intermittent stimulus, such as cerebral hypoxia, brain endothelial cells become
activated. Activated endothelial cells are highly synthetic and release a host of factors that can affect the activation of nearby cells. Despite the
continued presence of the stimulus, no new vessel growth occurs. Because no new vessels are formed there are no feedback signals to shut off
vascular activation endothelial cells, as occurs in physiologic angiogenesis. In AD reversible endothelial activation becomes irreversible
endothelial dysfunction. The vascular products of a permanently dysfunctional endothelium could cause neuronal injury/death directly or via
activation of microglia and/or astrocytes. (blue line) = feedback inhibition, (yellow lighting bolt) = Endothelial cell products.
Grammas Journal of Neuroinflammation 2011, 8:26
Page 5 of 12
functions could result in a noxious neuronal environ-
ment in the AD brain.
Synthetic functions of endothelial cells in health and
The endothelium is a highly synthetic interface that pro-
duces a large number of soluble factors; a partial list of
these products is shown in Table 1 . Endothelial
cell products have critical effects on neighboring cells.
In the walls of large vessels endothelial cell products
affect smooth muscle cell phenotype and contribute to
the evolution of the atherosclerotic plaque . Vascu-
lar-derived products of a permanently dysfunctional
endothelium could result in neuronal injury in neurode-
generative disease states. In the AD brain, an injured/
altered brain endothelial cell releases factors that are
injurious or toxic to neurons . Evidence for vascu-
lar-mediated neuronal cell death in AD is derived from
studies where direct co-culture of AD microvessels with
neurons or incubation of cultured neurons with condi-
tioned medium from microvessels results in neuronal
cell death . In contrast, vessels from elderly nonde-
mented donors are significantly less lethal and brain ves-
sels from younger donors are not neurotoxic. A study
using cultured brain endothelial cells shows that expo-
sure of these cells to the inflammatory proteins IL-1b
and LPS causes release factors that kill cholinergic neu-
rons . Also, inflammatory or oxidant injury of
brain endothelial cells in vitro leads to release of the
neurotoxic protease thrombin . Finally, the impor-
tance of the neurovascular unit as a mediator of neuro-
nal damage is highlighted by a recent study where
pericyte-deficient mice show an age-dependent vascular
damage that precedes neurodegenerative changes and
cognitive impairment .
In AD thrombin has been detected in the senile pla-
ques, characteristic of this disease . Traumatic
brain injury where neurons are exposed to high throm-
bin levels is associated with an increased incidence of
AD [152,153]. Some neurologic diseases, such as AD
and PD are characterized by increased levels of both
thrombin and the thrombin receptor protease-activated
receptor 1 (PAR-1) [154,155]. Furthermore, immunor-
eactivity for the major brain thrombin inhibitor, pro-
tease nexin-1 is found to be significantly decreased in
AD brains, particularly around blood vessels, suggesting
vascular release of thrombin . Our laboratory has
shown, by RT-PCR, that brain blood vessels isolated
from AD patients, but not age-matched controls,
synthesize thrombin . Thrombin is an example of a
vascular-derived factor relevant for AD because of its
pluripotent effects on inflammation, angiogenesis and
Thrombin causes endothelial activation and enhanced
expression and/or release of many proinflammatory pro-
teins including MCP-1 and ICAM-1, both of which are
upregulated in the cerebrovasculature in AD [54,91,157].
The cellular action of thrombin, potent angiogenic fac-
tor, on endothelial cells may represent an important
early event in activation of the normally quiescent
endothelial cells and initiation of the angiogenic cascade.
In endothelial cells, thrombin induces their alignment in
Matrigel, the expression and secretion of angiopoietin-2,
MMPs, IL-1b, IL-8 and the up-regulation of VEGF
receptors [158,159]. In addition, thrombin stimulates
upregulation of integrin aVb3 expression in endothelial
cells . These results are likely to be important for
understanding vascular pathology in AD as vascular
expression of VEGF, angiopoietin-2, MMPs, IL-1b, IL-8,
Table 1 Secretory/Expression Products of Endothelial
Extracellular matrix factorsProteases
collagen I, II, III, IV, VIII, XVIII tPA
Anti- and pro- coagulation factors
Factor V NO
EDHF PAI-1, PAI-2
Inflammatory Chemokines and CytokinesVasoconstriction factors
IL-1, IL-6, IL-8 TXA2/F2a
EDCFLTB4, C4, D4, E4
MHC II free radicals
*See text for references
Abbreviations used: prostacyclin (PGI2), anti-thrombin III (AT III), von
Willebrand factor (vWF), thromboxane A2 (TXA2), platelet-activating factor
(PAF), plasminogen activator inhibitor-1 (PAI-1), plasminogen activator
inhibitor-2 (PAI-2), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8),
leukotriene B4 (LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene
E4 (LTE4), monocyte chemoattractant protein-1 (MCP-1), monocyte
chemoattractant protein-2 (MCP-2), major histocompatibility complex class II
(MHC II), cell adhesion molecules (CAM), matrix metalloproteinases (MMPs),
tissue plasminogen activator (tPA), platelet-derived growth factor (PDGF),
endothelium derived growth factor (EDGF), fibroblast growth factor (FGF),
insulin-like growth factor (IGF), transforming growth factor beta (TGF-b),
granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte
colony-stimulating factor (G-CSF), nitric oxide (NO), prostacyclin/prostaglandin
E2 (PGI2/E2), endothelium derived hyperpolarizing factor (EDHF), thromboxane
A2/prostaglandin F2a (TXA2/F2a), endothelium derived contracting factor
Grammas Journal of Neuroinflammation 2011, 8:26
Page 6 of 12
and integrins are all upregulated in the AD brain
The multifunctional protease thrombin causes neuro-
nal cell death both in vitro and in vivo [161-169].
Thrombin causes rapid tau aggregation . Intracer-
ebroventricular administration of thrombin directly into
the rat brain results in neuronal cell death, glial scarring
and cognitive deficits . Activation or over-expres-
sion of the receptor PAR-1 has been shown to induce
motor neurodegeneration . Thrombin exerts direct
neurotoxicity by several mechanisms including reentry
into the cell cycle, induction of pro-apoptotic proteins,
as well as via NADPH oxidase mediated oxidative stress
Furthermore, the paracrine effects of thrombin
released from endothelial cells are also important
because of the ability of thrombin to activate other CNS
cells such as microglia and astrocytes. Pro-inflammatory
effects of thrombin on both microglia and astrocytes
have been demonstrated. Intranigral injection of throm-
bin injures the dopaminergic neurons in the substantia
nigra via thrombin-induced microglial activation and
release of nitric oxide . Thrombin has been shown
to stimulate the JAK2-STAT3 signaling pathway and
increase transcription of inflammation-associated genes
TNFa and inducible nitric oxide synthase in microglia
. In astrocytes, activation of PAR-1 by thrombin
leads to increased MMP-9 expression through regula-
tion of ERK1/2 . Thus, vascular-derived thrombin
may directly injure neurons or affect neuronal viability
indirectly via activation of microglia and astrocytes in
the neurovascular unit.
Neurovascular unit dysfunction and amyloid transport
The neurovascular unit is an emerging concept that
emphasizes the interactions among glial, neuronal and
vascular elements [17,174-177]. Homeostatic signaling
within the neurovascular unit is critical to normal brain
function. The hemodynamic communication between
neurons and the cerebrovasculature is necessary to effi-
ciently couple CBF to neuronal activation. Dysfunctional
cell-cell signaling in the neurovascular unit is increas-
ingly implicated as characteristic feature of CNS diseases
[19,175,177-179]. Structural and functional integrity of
the CNS depends on the coordinated activity of the neu-
rovascular unit to not only couple neural activity to CBF
but also to regulate transport across the blood-brain
barrier. There is some evidence that disturbance of the
functional relationships among the cells of the neurovas-
cular unit is an early event in AD . Functional MRI
studies suggest that alterations in CBF regulation in
response to cognitive tasks may be a predictor of risk
for developing AD .
An important function of the blood-brain barrier that
may go awry in AD is regulation of the brain pool of
Ab. Brain Ab, which is in equilibrium with plasma and
CSF Ab, is modulated by influx of soluble Ab across the
blood-brain barrier via its interaction with the receptor
for advanced glycation end products (RAGE) and efflux
via the low density lipoprotein receptor on brain
endothelial cells. Accumulating evidence from patients
and animal models of AD suggests that vulnerable
brains may suffer from an increase in influx receptors
(RAGE) and/or a decrease in efflux receptors (lipopro-
tein receptor-related protein) [180,181]. Multiple patho-
genic cascades in the neurovascular unit may contribute
to faulty clearance of amyloid across the blood-brain
barrier which may amplify neuronal dysfunction and
injury in AD.
Ab has toxic effects on endothelial cells both via direct
mechanisms and by inducing local inflammation
[94,96-98]. The cerebral microvasculature is central to a
destructive cycle of events where inflammation precedes
Ab deposition and Ab in turn promotes release of
inflammatory mediators. The cerebrovascular-derived
inflammatory protein thrombin, via stimulation of func-
tionally active thrombin (PAR-1 and PAR-3) receptors
 on brain endothelial cells can further stimulate
inflammatory processes in an autocrine fashion. Throm-
bin in vitro can stimulate production of the amyloid
precursor protein (APP) and cleavage of APP into frag-
ments that are found in amyloid plaques of AD brains
[183,184]. In this manner, Ab and thrombin may com-
bine to stimulate a deleterious feed-forward cycle result-
ing in neuronal cell death in AD.
Despite intense research efforts, the enigma that is AD
continues to present daunting challenges for effective
therapeutic intervention. The lack of disease-modifying
therapies may, in part, be attributable to the narrow
research focus employed to understand this complex dis-
ease. Most human and animal studies in the AD field
reflect a “neurocentric” view and have focused on the Ab
protein as the primary neurotoxic species involved in dis-
ease pathogenesis. Because of its classification as a non-
vascular dementia, the role of neuro-vascular interactions
in the evolution of neuronal injury in AD brain has been
underappreciated. Nevertheless, increasing literature sup-
ports a vascular-neuronal axis in AD as shared risk fac-
tors for both AD and atherosclerotic cardiovascular
disease implicate vascular mechanisms in the develop-
ment and/or progression of AD. The endothelium is a
common target for all cardiovascular risk factors, and
functional impairment of the vascular endothelium in
response to injury occurs long before the development of
overt disease. Chronic inflammation, a feature of AD, is
tightly linked to diseases associated with endothelial dys-
function. The cerebromicrocirculation is a dynamic
Grammas Journal of Neuroinflammation 2011, 8:26
Page 7 of 12
interface serving as both a source of, and a target for,
inflammatory proteins. Brain endothelial cells regulate
the neuronal milieu both by their synthetic functions as
well as by their blood-brain barrier function. Therefore,
disturbance in cerebrovascular metabolic or transport
functions could result in a noxious neuronal environment
in the AD brain. The cerebral microvasculature is central
to a destructive cycle of events where inflammation pre-
cedes Ab deposition and Ab in turn promotes release of
inflammatory mediators. In this review we summarize
data that support a new paradigm of disease pathogen-
esis, based on endothelial dysfunction and release of plur-
ipotent mediators with effects on inflammation, vascular
activation/angiogenesis and neurotoxicity. The activated/
dysfunction brain endothelium is a novel, unexplored
therapeutic target in AD.
Acknowledgements and Funding
Sources of support: This work was supported in part by grants from the
National Institutes of Health (AG15964, AG020569 and AG028367). Dr.
Grammas is the recipient of the Shirley and Mildred Garrison Chair in Aging.
The author gratefully acknowledges the helpful suggestions of Joseph
Martinez and the secretarial assistance of Terri Stahl.
PG wrote the manuscript and has approved the final version of the
The author declares that they have no competing interests.
Received: 6 January 2011 Accepted: 25 March 2011
Published: 25 March 2011
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Cite this article as: Grammas: Neurovascular dysfunction, inflammation
and endothelial activation: Implications for the pathogenesis of
Alzheimer’s disease. Journal of Neuroinflammation 2011 8:26.
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