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Current Pharmaceutical Design

Volume 14 Issue 30
ISSN: 1381-6128
eISSN: 1873-4286

 

   All Titles

  Amyloid β -Protein Assembly as a Therapeutic Target of Alzheimer's Disease
  pp.3231-3246 (16) Authors: Ghiam Yamin, Kenjiro Ono, Mohammed Inayathullah, David B. Teplow
 
 
      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
  Affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA.
 
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