Amyloid beta-protein assembly as a therapeutic target of Alzheimer's disease.
Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta 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 Abeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing 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.
Yamin
Ghiam
G
Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA.
Ono
Kenjiro
K
Inayathullah
Mohammed
M
Teplow
David B
DB
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D007167:Immunotherapy; D028321:Plant Preparations / Q000627:therapeutic use; D017510:Protein Folding; D054852:Small Molecule Libraries / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D028321:Plant Preparations; D054852:Small Molecule Libraries