Membrane perturbation by the neurotoxic alzheimer amyloid fragment β25‐35 requires aggregation and β‐sheet formation

The β‐amyloid peptide (βAP) is a major proteinaceous component of senile plaques and cerebrovascular amyloid deposits found in the brain of patients with Alzheimer's disease. βAP is reported to be neurotoxic only when it forms β‐sheet structure and aggregates. In the present study, we report that the neurotoxic core of βAP, βAP‐25‐35 (β25‐35), perturbs liposome membranes, induces membrane current, and exhibits hemolytic activity only in a buffer condition where the peptide forms β‐sheet structure and spontaneously aggregates. In contrast, β25‐35 in its monomeric random coil structure does not perturb lipid membranes significantly, and exhibits no hemolytic activity. Also, the membrane current was inhibited by Congo Red. The ability of β25‐35 to interact with membranes highly correlates with its neurotoxicity reported previously. These results suggest that membrane perturbation by aggregated β25‐35 constitutes the molecular basis of the peptide's neurotoxicity.