Inhibiting the conversion of soluble amyloid-beta peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer's disease therapy

Alzheimer's disease is a degenerative disorder of the brain for which there is no cure or effective treatment. Recent studies suggest that cerebral am yloid plaques are central to the disease process. However, it is not clear which of the species going from the normal soluble amyloid-beta peptide to the mature amyloid plaque is the toxic agent in the brain. Therefore, an at tractive therapeutic strategy for Alzheimer's disease is to block the early steps involving the pathological conversion of the soluble peptide into th e abnormally folded oligomeric intermediate precursor of the amyloid fibril s. We have engineered synthetic beta -sheet breaker peptides to bind amyloi d-beta peptide, stabilize the normal conformation and destabilize the beta -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 beta -sheet breaker peptide may be useful for blocking the pa thway that lead to the formation of cerebral amyloid deposits. It remains t o be proved that inhibition of the defective folding of amyloid-beta peptid e and/or amyloid plaque deposition could be beneficial for the therapeutic treatment of Alzheimer's disease.