STRUCTURE-ACTIVITY ANALYSES OF BETA-AMYLOID PEPTIDES - CONTRIBUTIONS OF THE BETA-25-35 REGION TO AGGREGATION AND NEUROTOXICITY

The neurodegeneration of Alzheimer's disease has been theorized to be mediated, at least in part, by insoluble aggregates of beta-amyloid pr otein that are widely distributed in the form of plaques throughout br ain regions affected by the disease. Previous studies by our laborator y and others have demonstrated that the neurotoxicity of beta-amyloid in vitro is dependent upon its spontaneous adoption of an aggregated s tructure. In this study, we report extensive structure-activity analys es of a series of peptides derived from both the proposed active fragm ent of beta-amyloid, beta 25-35, and the full-length protein, beta 1-4 2. We examine the effects of amino acid residue deletions and substitu tions on the ability of beta-amyloid peptides to both form sedimentabl e aggregates and induce toxicity in cultured hippocampal neurons. We o bserve that significant levels of peptide aggregation are always assoc iated with significant beta-amyloid-induced neurotoxicity. Further, bo th N- and C-terminal regions of beta 25-35 appear to contribute to the se processes. In particular, significant disruption of peptide aggrega tion and toxicity result from alterations in the beta 33-35 region. In beta 1-42 peptides, aggregation disruption is evidenced by changes in both electrophoresis profiles and fibril morphology visualized at the light and electron microscope levels. Using circular dichroism analys is in a subset of peptides, we observed classic features of beta-sheet secondary structure in aggregating, toxic beta-amyloid peptides but n ot in nonaggregating, nontoxic beta-amyloid peptides. Together, these data further define the primary and secondary structures of beta-amylo id that are involved in its in vitro assembly into neurotoxic peptide aggregates and may underlie both its pathological deposition and subse quent degenerative effects in Alzheimer's disease.