MEMBRANE PERTURBATION BY THE NEUROTOXIC ALZHEIMER AMYLOID FRAGMENT BETA-25-35 REQUIRES AGGREGATION AND BETA-SHEET FORMATION

The beta-amyloid peptide (beta AP) is a major proteinaceous component of senile plaques and cerebrovascular amyloid deposits found in the br ain of patients with Alzheimer's disease. beta AP is reported to be ne urotoxic only when it forms beta-sheet structure and aggregates. In th e present study, we report that the neurotoxic core of beta AP, beta A P-25-35 (beta 25-35), perturbs liposome membranes, induces membrane cu rrent, and exhibits hemolytic activity only in a buffer condition wher e the peptide forms beta-sheet structure and spontaneously aggregates. In contrast, beta 25-35 in its monomeric random coil structure does n ot perturb lipid membranes significantly, and exhibits no hemolytic ac tivity. Also, the membrane current was inhibited by Congo Red. The abi lity of beta 25-35 to interact with membranes highly correlates with i ts neurotoxicity reported previously. These results suggest that membr ane perturbation by aggregated beta 25-35 constitutes the molecular ba sis of the peptide's neurotoxicity.