Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 14, Issue 30, Pages 3231-3246Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161208786404137
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Funding
- UCLA Graduate Research Mentorship Program
- UCLA Chemistry-Biology Interface (CBI)
- Japan Human Science Foundation
- Eli Lilly Japan
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- State of California Alzheimer's Disease Research Fund [07-65806]
- Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarkers at UCLA
- NIH [AG027818, AT004511]
- NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE [P01AT004511] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG027818] Funding Source: NIH RePORTER
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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 (A beta), a 40-42 amino acid peptide. The folding of A beta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. A beta is formed through cleavage of the A beta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the A beta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting A beta 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 A beta 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.
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