this article - The Angiogenesis Foundation

Alzheimer’s disease and angiogenesis
Anthony H Vagnucci Jr, William W Li
Despite enormous investigative efforts, the pathological basis for Alzheimer’s disease remains unclear. Suggested
mechanisms for the disorder include cerebral hypoperfusion, inflammation, gene polymorphisms, and molecular lesions
in the brain. In this Hypothesis, we argue that the vascular endothelial cell has a central role in the progressive
destruction of cortical neurons in Alzheimer’s disease. In Alzheimer’s disease, the brain endothelium secretes the
precursor substrate for the -amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons. Large
populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation. Results of
epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2receptor blockers, or calcium-channel blockers seems to prevent Alzheimer’s disease. We think this benefit is largely
due to these drugs’ ability to inhibit angiogenesis. If Alzheimer’s disease is an angiogenesis-dependent disorder, then
development of antiangiogenic drugs targeting the abnormal brain endothelial cell might be able to prevent and treat
this disease. We suggest several laboratory and clinical approaches for testing our hypothesis.
Alzheimer’s disease is one of the most common diseases of
modern society. Affecting 10% of the world’s population,
this progressive neurodegenerative disorder causes untold
human suffering and consumes more than US$100 billion
per year in health-care costs. Although the amyloid
plaque, which contains among other elements, -amyloid
peptide fragments, has been identified as a primary
pathological lesion of Alzheimer’s disease, how these
plaques form in the brain remains unclear. Heredity, gene
inflammation, and molecular lesions have all been
suggested as potential mechanisms.1 However, an
integrated understanding of the disease with clear
Consequently, treatments are restricted to ameliorating
the symptoms of dementia by increasing brain levels of
acetylcholine with drugs such as tacrine, donepezil,
rivastigmine, or galantamine.
Results of epidemiological studies suggest that chronic
use of certain drugs significantly decreases the risk of
Alzheimer’s disease in high-risk populations (table 1).2–9
Such drugs include non-steroidal anti-inflammatory
agents (NSAIDs), lipid-lowering statins, histamine H2receptor blockers, and calcium-channel blockers. The
clinical data are very persuasive. For example, results of a
study of 6989 patients who did not have dementia at
baseline showed that the relative risk of Alzheimer’s
disease fell to 0·20 with long-term (2-year) NSAID use.2
The results of at least 17 epidemiological studies from
nine countries corroborate these results, including the
original observations.3,6 Hence, brain inflammation has
become a major focus for Alzheimer’s disease research.
Lancet 2003; 361: 605–08
Department of Psychiatry, The Cambridge Hospital, Cambridge,
MA, USA (A H Vagnucci Jr MD); Institute of Advanced Studies,
Angiogenesis Foundation, Cambridge, MA (W W Li MD); and Harvard
Medical School, Boston, MA (A H Vagnucci Jr, W W Li)
Correspondence to: Dr William W Li, The Angiogenesis Foundation,
PO Box 382111, Cambridge, MA 02238, USA
(e-mail: [email protected])
THE LANCET • Vol 361 • February 15, 2003 •
Class of drug
Relative risk reduction
Breitner and colleagues5
Breitner and colleagues3
McGeer and colleagues6
Stewart and colleagues7
Forette and colleagues4
NSAIDs or steroids
H2 blockers
Lipid-lowering agents
Lipid-lowering agents
Wolozin and colleagues8
Jick and colleagues9
in’t Veld and colleagues2
Table 1: Evidence for drugs that reduce the risk of Alzheimer’s
disease with long-term use
Brain inflammation cannot, however, explain the risk
reduction conferred by drugs that lack substantial antiinflammatory activity. We have noted that putative
Alzheimer’s disease-preventive agents (table 2) inhibit
angiogenesis, which led us to consider the role of the brain
vascular endothelial cell. Endothelial cells respond to both
hypoxia and inflammation by undergoing angiogenesis.
Mediated by cytokine growth factors, this process involves
the activation of endothelial cells from pre-existing
venules to form tubular networks that augment the local
microcirculation by bringing oxygen and nutrients to
compromised tissue. The endothelium also exerts direct
local effects by producing at least 20 paracrine factors that
act on adjacent cells. Although many of these factors are
antiapoptotic survival signals, microvessels in diseased
tissues also secrete toxic substances including neurotoxins
and amyloid precursors.10,11
Anti-inflammatory activity
Antiangiogenic activity
H2 blocker
+ and – denote the biological activity of each agent.
Table 2: Drugs associated with decreased risk of Alzheimer’s
disease or decreased formation of -amyloid peptide
For personal use. Only reproduce with permission from The Lancet Publishing Group.
A second mechanism of angiogenic
injury in Alzheimer’s disease is the
secretion of a soluble, neuroselective
peptide toxin that kills primary cortical
and cerebellar granular neurons. This
neurotoxin is secreted in large
quantities from microvessels taken
from brains of Alzheimer’s disease
patients, by contrast with much smaller
quantities secreted by vessels from
brains of elderly people without
dementia.10 Brain microvessels of
young healthy patients do not secrete
this toxin. Thus, compensatory
attempts to neovascularise hypoxic
regions in the brain in Alzheimer’s
disease promote deleterious endothelial-mediated
giving new meaning to the term
pathological angiogenesis. The genetic
or epigenetic factor or factors
Figure 1: Microvascular density in brains in Alzheimer’s disease (A) and in normal
predisposing subgroups of elderly
age-matched controls (B)
Vascular basement membranes are shown by immunohistochemical staining of heparan sulphate
patients to this harmful vascular
proteoglycan. Reprinted from reference 14. Copyright (1990), with permission from Elsevier Science.
phenotype remain unknown.
How does angiogenesis occur in the
brain in Alzheimer’s disease? At least five overlapping
mechanisms drive this process (figure 3).
We propose that Alzheimer’s disease is mediated by
pathological angiogenesis. Neovascularisation in the
● Hypoperfusion in the elderly brain leads to hypoxia, a
brain in Alzheimer’s disease occurs in response to
stimulus that induces expression of vasoactive mediators
impaired cerebral perfusion (oligaemia) and vascular
such as nitric oxide, hypoxia-inducible-factor-1
injury (inflammation). Morphological and biochemical
(HIF 1), and VEGF—one of the most potent angiogenic
evidence for this process include regionally increased
cytokines. Increased VEGF expression is seen in reactive
capillary density, vascular loop formation, glomeruloid
astrocytes and perivascular deposits of Alzheimer’s disease
vascular structure formation, and expression of
angiogenic factors: vascular endothelial growth factor
● The neurofibrillary tangles of Alzheimer’s disease,
(VEGF), transforming growth factor (TGF ), and
thought to be secondary to -amyloid accumulation,
tumour necrosis factor (TNF ) (figure 1).12–15 We
contain heparan sulphate proteoglycans, a substrate that
binds avidly to basic fibroblast growth factor (bFGF),
suggest that angiogenic activation of the brain
another angiogenic cytokine.1,20
endothelium in Alzheimer’s disease leads to deposition of
the -amyloid plaque and secretion of a neurotoxic
● Thrombin itself directly stimulates angiogenesis in
peptide that kills cortical neurons.
regions of injured vascular endothelium.18
Alzheimer’s disease is linked with the microcirculation.
● Inflammatory mediators found in brains in Alzheimer’s
Ultrastructural studies have shown that brain microvessels
disease, such as TNF , interleukin 6, and monocyte
are closely associated with -amyloid plaques, and that
chemoattractant protein-1, stimulate angiogenesis.21 In
Alzheimer’s disease brain capillaries
contain preamyloid deposits.16 The
-amyloid plaque generates reactive
oxygen species that damage brain
endothelium.17 A thrombogenic region
-amyloid plaque
develops in the vessel wall, leading to
intravascular accumulation of thromO2
bin. Thrombin activates vascular
endothelial cells to secrete amyloid
precursor protein via a receptormediated, protein kinase C-dependent
EC damage
pathway.11,18 Progressive deposition of
and thrombin
amyloid precursor protein leads to
accumulation of the -amyloid plaque,
which generates more reactive oxygen
species and induces further endothelial
damage. Thrombin accumulates and
stimulates even more angiogenesis and
production of amyloid precursor
protein. We postulate that this cycle of
endothelial-dependent events consecreted
tributes to -amyloid accumulation in
the brain of people with Alzheimer’s Figure 2: How the endothelium damages the brain in Alzheimer’s disease
disease and to neuronal death APP=amyloid precursor protein. EC=endothelial cell. Reprinted with permission from the
(figure 2).
Angiogenesis Foundation.
THE LANCET • Vol 361 • February 15, 2003 •
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Copyright © Angiogenesis Foundation. 2002.
Alzheimer’s disease, these factors may
be induced by neuronal death, by
-amyloid binding of the C1q
and monocytes
component of the complement cascade,
and by peroxidative and free radical
injury of microvessels, among other
mechanisms. Invading macrophages
and monocytes also release the
angiogenic growth factors VEGF,
bFGF, and platelet-derived growth
factor (PDGF).
● The
gene expression of an
endogenous angiogenesis inhibitor,
thrombospondin, is reduced near focal
Alzheimer’s disease lesions, leading to a
proangiogenic state in those sites.22
neovascularisation bear remarkable
similarity to the plethora of signals
leading to tumour angiogenesis in
Why does angiogenesis lead to
plaque formation in the brain in
Alzheimer’s disease but not with multiinfarct
speculate that the brain endothelium in Figure 3: Angiogenesis in the brain in Alzheimer’s disease
Alzheimer’s disease possesses unique Reprinted with permission from the Angiogenesis Foundation.
genotypic and phenotypic features not
present in other brains. Such endothelial heterogeneity is
be administered to investigate whether pathological
seen in comparison of abnormal with normal tissues.24
features are ameliorated. Conversely, animals can be
transfected with an adenovirus encoding the gene for
Therefore, whereas angiogenesis occurs in response to
VEGF to establish whether angiogenesis stimulation
brain ischaemia and inflammation in both Alzheimer’s
accelerates pathological changes related to Alzheimer’s
disease and stroke patients, distinct pathological changes
result in Alzheimer’s disease.
The microvessel neurotoxin can be studied by
Our hypothesis explains the puzzle posed by seemingly
examination of endothelial cells grown in tissue culture
unrelated drugs that confer protection against Alzheimer’s
that were derived from Alzheimer’s disease brain tissue.
disease. Anti-inflammatory drugs, H2-receptor blockers,
Does the addition of angiogenic growth factors, such as
antihypertensives, and statins can all inhibit angiobFGF or VEGF, increase neurotoxin secretion by
genesis.25–27 We propose that the substantial reduction in
endothelial cells? Can antiangiogenic drugs suppress
the risk of Alzheimer’s disease noted in the results of
neurotoxin production? Genomic studies of Alzheimer’s
population-based studies is predominantly due to the
disease-derived endothelium could identify genes that are
antiangiogenic actions of these drugs on the endothelial
uniquely expressed in Alzheimer’s disease, which could be
cell. This mechanism does not, of course, exclude other
new molecular targets for therapy.24
potential mechanisms of drugs, such as NSAIDS or
statins, which might also directly suppress neuronal
Clinical prevention studies can be done in patients at
production of -amyloid plaque. Many of these agents
high risk for Alzheimer’s disease by use of angiogenesis
might possess relatively small antiangiogenic effects
inhibitors. Many oral antiangiogenic agents are undergoing
compared with the potent and specific angiogenesis
oncological trials, such as thalidomide, AE-941, PTK787,
inhibitors in clinical development for the treatment of
endostatin, and BMS275291.23 A randomised, proscancer, retinopathies, and psoriasis.23
pective, double-blinded trial of these agents can be done in
an Alzheimer’s disease prevention trial. Patients receiving
Although Alzheimer’s disease is without doubt a
an antiangiogenic drug would be expected to have a lower
complex and multifactorial disorder, we think that brain
incidence of Alzheimer’s disease, compared with a placebo
angiogenesis should become a new focus for basic and
control group. Intervention trials could be done with the
clinical investigation. Even as researchers continue to
expected endpoint of disease stabilisation. A drug could
unravel the mechanisms behind Alzheimer’s disease,
exist that provided protection against both Alzheimer’s
patients at high risk for the disease might benefit from the
disease and cancer. Such trials would be lengthy and
judicious use of commonly-used drugs which possess
complex to manage, and therefore require strong
antiangiogenic activity.
supportive preclinical evidence from laboratory studies.
The sheer magnitude of Alzheimer’s disease in the ageing
Testing the hypothesis
population, however, should provide incentive for
The role of angiogenesis in Alzheimer’s disease can be
researchers, clinical investigators, and industry.
tested in laboratory and clinical studies. A transgenic
mouse (presenilin/amyloid precursor protein) model for
Alzheimer’s disease induces amyloid deposition, microglia
Conflict of interest statement
and astrocyte activation, and brain inflammation.28 In this
None declared.
system, angiogenesis markers (such as VEGF or v3 and
v5 integrins) can be studied by immunohistochemistry,
and temporally and spatially correlated with -amyloid
We thank R Rohrbaugh, V W Li, A H Vagnuccci Sr, and G Gehr for
deposition and neuronal death. Antiangiogenic agents can
discussion and review of the manuscript; A Grivas for medical
THE LANCET • Vol 361 • February 15, 2003 •
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Copyright © Angiogenesis Foundation. 2002.
illustrations; and J Lee-Olsen for library assistance. This study was
funded, in part, by the Angiogenesis Foundation, a non-profit
organisation, which had no role in the writing of this report.
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