Neurodegeneration induced by β-amyloid peptides in vitro: The role of peptide assembly state

Abstract

The progressive neurodegeneration of Alzheimer's disease has been hypothesized to be mediated, at least in part, by β-amyloid protein. A relationship between the aggregation state of β-amyloid protein and its ability to promote degeneration in vitro has been previously suggested. To evaluate this hypothesis and to define a structure-activity relationship for β-amyloid, aggregation properties of an overlapping series of synthetic β-amyloid peptides (βAPs) were investigated and compared with βAP neurotoxic properties in vitro. Using light microscopy, electrophoresis, and ultracentrifugation assays, we found that few βAPs assembled into aggregates immediately after solubilization, but that over time peptides containing the highly hydrophobic β29-35 region formed stable aggregations. In short-term neuronal cultures, toxicity was associated specifically with those βAPs that also exhibited significant aggregation. Further, upon the partial reversal of β1-42 aggregation, a concomitant loss of toxicity was observed. A synthetic peptide derived from a different amyloidogenic protein, islet amyloid polypeptide, exhibited aggregation but not toxicity, suggesting that βAP-induced neurotoxicity in vitro is not a nonspecific reaction to aggregated protein. The correlation between βAP aggregation and neurotoxicity was also observed in long-term neuronal cultures but not in astrocyte cultures. These data are consistent with the hypothesis that β-amyloid protein contributes to neurodegeneration in Alzheimer's disease.