Amyloid β -Protein Assembly as a Therapeutic Target of Alzheimer's Disease

Authors: Yamin, Ghiam; Ono, Kenjiro; Inayathullah, Mohammed; Teplow, David B.

Source: Current Pharmaceutical Design, Volume 14, Number 30, October 2008 , pp. 3231-3246(16)

Publisher: Bentham Science Publishers

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Abstract:

Alzheimer's 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

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138161208786404137

Affiliations: 1: Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA.

Publication date: 2008-10-01

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Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Amyloid β -Protein Assembly as a Therapeutic Target of Alzheimer's Disease

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