The interaction of beta-amyloid protein with cellular membranes stimulates its own production

Gradual changes in steady-state levels of beta amyloid peptides (A beta) in brain are considered an initial step in the amyloid cascade hypothesis of Alzheimer's disease. A beta is a product of the secretase cleavage of amyloid precursor protein (APP). There is evidence that the membrane lipid environment may modulate secretase activity and alters its function. Cleavage of APP strongly depends on membrane properties. Since A beta perturbs cell membrane fluidity, the cell membrane may be the location where the neurotoxic cascade of A beta is initiated. Therefore, we tested effects of oligomeric A beta on membrane fluidity of whole living cells, the impact of exogenous and cellular A beta on the processing of APP and the role of GM-1 ganglioside. We present evidence that oligoA beta((1-40)) stimulates the amyloidogenic processing of APP by reducing membrane fluidity and complexing with GM-I ganglioside. This dynamic action of A beta may start a vicious circle. where endogenous A beta stimulates its own production. Based on our novel findings, we propose that oligoA beta((1-40)) accelerates the proteolytic cleavage of APP by decreasing membrane fluidity. (C) 2009 Elsevier B.V. All rights reserved.