SECONDARY STRUCTURE OF AMYLOID BETA-PEPTIDE CORRELATES WITH NEUROTOXIC ACTIVITY IN-VITRO

Amyloid beta peptide (Abeta), the major protein constituent of senile plaques in patients with Alzheimer's disease, is believed to facilitat e the progressive neurodegeneration that occurs in the latter stages o f this disease. Early attempts to characterize the structure-activity relationship of Abeta toxicity in vitro were compromised by the inabil ity to reproducibly elicit Abeta-dependent toxicity across different l ots of chemically equivalent peptides. In this study we used CD spectr oscopy to demonstrate that Abeta secondary structure is an important d eterminant of Abeta toxicity. Solubilized Abeta was maximally toxic wh en the peptide adopted a beta-sheet conformation. Three of the four Ab eta lots tested had a random coil conformation and were weakly toxic o r inactive, whereas the single Abeta lot exhibiting toxic activity at low peptide concentrations had significant beta-sheet structure. Incub ation of the weakly toxic Abeta lots in aqueous stock solutions for se veral days before use induced a time-dependent conformational transiti on from random coil to beta-sheet and increased Abeta toxicity in thre e different toxicity assays. Furthermore, the secondary structure of p reincubated Abeta was dependent upon peptide concentration and pH, so that beta-sheet structures were attenuated when peptide solutions were diluted or buffered at neutral and basic pH. Our data could explain s ome of the variable toxic activity that has been associated with Abeta in the past and provide additional support for the hypothesis that Ab eta can have a causal role in the molecular neuropathology of Alzheime r's disease.