Neurovascular mechanisms of Alzheimer's neurodegeneration

• Published in: Trends in neurosciences (Regular ed.) Vol. 28; no. 4; pp. 202 - 208
• Main Author: Zlokovic, Berislav V.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2005; Elsevier Science; Elsevier Sequoia S.A
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Biological and medical sciences; Blood; Blood-Brain Barrier - physiopathology; Brain; Brain - blood supply; Brain - pathology; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebrovascular Circulation - physiology; Cognition & reasoning; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Models, Neurological; Nerve Degeneration - etiology; Nerve Degeneration - pathology; Neurology; Peptides; Vertebrates: nervous system and sense organs; Nervous system diseases; Senescence; Cognitive disorder; Alzheimer disease; Central nervous system; Review; Blood brain barrier; Cerebral disorder; Dysfunction; Central nervous system disease; Degenerative disease; Repair; Apoptosis
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2005.02.001

In contrast to traditional neuroncentric views of Alzheimer's disease (AD), recent findings indicate that neurovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Here, I propose the neurovascular hypothesis of AD, suggesting that faulty clearance of amyloid β peptide (Aβ) across the blood–brain barrier (BBB), aberrant angiogenesis and senescence of the cerebrovascular system could initiate neurovascular uncoupling, vessel regression, brain hypoperfusion and neurovascular inflammation. Ultimately, this would lead to BBB compromise, to chemical imbalance in the neuronal environment and to synaptic and neuronal dysfunction, injury and loss. Based on the neurovascular hypothesis, I suggest an array of new potential therapeutic approaches that could be developed for AD, to enhance Aβ clearance and neurovascular repair, and to protect the neurovascular unit from divergent inducers of injury and apoptosis.