Amyloid β-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 (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.