HYPOTHESIS Hypothesis 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 polymorphisms, cerebral hypoperfusion, brain inflammation, and molecular lesions have all been suggested as potential mechanisms.1 However, an integrated understanding of the disease with clear recommendations for interventions is lacking. 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 • www.thelancet.com Reference 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 NSAIDs Aspirin Calcium-channel blockers Lipid-lowering agents Lipid-lowering agents NSAIDs 0·24 0·14 0·50 0·74 0·50 Wolozin and colleagues8 Jick and colleagues9 in’t Veld and colleagues2 0·60 0·29 0·20 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 Agent Anti-inflammatory activity Antiangiogenic activity Lovastatin Simvastatin Pravastatin Sulindac Diclofenac Indometacin Aspirin H2 blocker Nitrendipine Nimodipine – – – + + + + – – – + + + + + + + + + + + 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 605 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 neuronal killing, giving new meaning to the term A B 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 Hypothesis 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 patients.19 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 accumulation of the -amyloid plaque, Neuron which generates more reactive oxygen damage species and induces further endothelial APP damage. Thrombin accumulates and stimulates even more angiogenesis and production of amyloid precursor Soluble protein. We postulate that this cycle of peptide neurotoxin 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. 606 THE LANCET • Vol 361 • February 15, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group. Copyright © Angiogenesis Foundation. 2002. HYPOTHESIS Alzheimer’s disease, these factors may be induced by neuronal death, by Macrophages -amyloid binding of the C1q and monocytes component of the complement cascade, VEGF and by peroxidative and free radical bFGF injury of microvessels, among other PDGF mechanisms. Invading macrophages and monocytes also release the angiogenic growth factors VEGF, bFGF, and platelet-derived growth factor (PDGF). VEGF ● The gene expression of an endogenous angiogenesis inhibitor, HIF1 thrombospondin, is reduced near focal Alzheimer’s disease lesions, leading to a Hypoxia proangiogenic state in those sites.22 These redundant stimuli for neovascularisation bear remarkable O2 similarity to the plethora of signals leading to tumour angiogenesis in O2 cancer.23 Why does angiogenesis lead to O2 plaque formation in the brain in Alzheimer’s disease but not with multiinfarct vascular dementia? We 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 disease. 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, Acknowledgments 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 • www.thelancet.com 607 For personal use. Only reproduce with permission from The Lancet Publishing Group. Copyright © Angiogenesis Foundation. 2002. HYPOTHESIS HYPOTHESIS 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. 15 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 1999; 399 (suppl): A23–31. in’t Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345; 21: 1515–21. Breitner JC, Welsh KA, Helms MJ, et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 1995; 16: 523–30. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. 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