Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

• Published in: Molecular psychiatry Vol. 14; no. 5; pp. 469 - 486
• Main Authors: Bates, K A, Verdile, G, Li, Q-X, Ames, D, Hudson, P, Masters, C L, Martins, R N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2009; Nature Publishing Group
• Subjects: Adult and adolescent clinical studies; Advanced glycosylation end products; Alzheimer Disease - diagnosis; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Amyloid beta-Protein Precursor - physiology; Animals; Apolipoproteins; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Biological transport; Blood-brain barrier; Blood-Brain Barrier - physiopathology; Cell death; Cognitive ability; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development and progression; Diagnostic tests; Drug Design; feature-review; Genetic aspects; Glycosylation; Humans; Hypotheses; Medical sciences; Medicine; Medicine & Public Health; Molecular chaperones; Neurodegenerative diseases; Neuroimaging; Neurology; Neurosciences; Organic mental disorders. Neuropsychology; Pathogenesis; Peptides; Pharmacotherapy; Physiological aspects; Positron emission tomography; Protease Nexins; Protein Transport - physiology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Cell Surface - physiology; Receptors, Lipoprotein - metabolism; Toxicity; β-Amyloid; apolipoprotein E; chaperone proteins; dementia; blood–brain barrier; transport; blood-brain barrier; Nervous system diseases; Alzheimer disease; Biological transport; Central nervous system; Clearance; Blood brain barrier; Encephalon; Cerebral disorder; Treatment; Apolipoprotein E; β Amyloid protein; Central nervous system disease; Degenerative disease; Diagnosis
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2008.96

Currently, the ‘amyloid hypothesis’ is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-β (Aβ) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Aβ is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Aβ leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Aβ are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Aβ clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Aβ ELISAs are discussed, as are the more promising results of Aβ imaging by positron emission tomography. Current knowledge of Aβ-binding proteins and Aβ-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood–brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Aβ remains an attractive therapeutic strategy, and improved understanding of Aβ clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.