Inhibiting the conversion of soluble amyloid-β peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer's disease therapy
Abstract:Alzheimer's disease is a degenerative disorder of the brain for which there is no cure or effective treatment. Recent studies suggest that cerebral amyloid plaques are central to the disease process. However, it is not clear which of the species going from the normal soluble amyloid-β peptide to the mature amyloid plaque is the toxic agent in the brain. Therefore, an attractive therapeutic strategy for Alzheimer's disease is to block the early steps involving the pathological conversion of the soluble peptide into the abnormally folded oligomeric intermediate precursor of the amyloid fibrils. We have engineered synthetic β-sheet breaker peptides to bind amyloid-β peptide, stabilize the normal conformation and destabilize the β-sheet rich structure of the potentially toxic intermediates and hence the formation of amyloid plaques. Results in vitro, in cell culture and in vivo suggest that β-sheet breaker peptide may be useful for blocking the pathway that lead to the formation of cerebral amyloid deposits. It remains to be proved that inhibition of the defective folding of amyloid-β peptide and/or amyloid plaque deposition could be beneficial for the therapeutic treatment of Alzheimer's disease.
Document Type: Original Article
Affiliations: Serono Pharmaceutical Research Institute, 14 Chemin-des-Aulx, 1228 Plan les Ouates, Geneva, Switzerland
Publication date: 2000-12-01