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Current Pharmaceutical Design
ISSN (Print): 1381-6128
ISSN (Online): 1873-4286
VOLUME: 14
ISSUE: 30
DOI: 10.2174/138161208786404137      Price:  $58









Amyloid β -Protein Assembly as a Therapeutic Target of Alzheimers Disease

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Author(s): Ghiam Yamin, Kenjiro Ono, Mohammed Inayathullah and David B. Teplow
Pages 3231-3246 (16)
Abstract:
Alzheimers disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid β-protein (Aβ), a 40-42 amino acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Aβ is formed through cleavage of the Aβ precursor protein by two endoproteinases, β-secretase and γ-secretase, that cleave the Aβ N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Aβ production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Aβ assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydratecontaining compounds, polyamines, “drug-like” compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.
Keywords:
Alzheimer's disease (AD), amyloid β-protein (Aβ), peptide, neurotoxicity, metal chelators, osmolytes), Immunotherapy
Affiliation:
Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA.