Amyloid β interacts with the amyloid precursor protein:: a potential toxic mechanism in Alzheimer's disease

Amyloid beta protein (A beta) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of A beta is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of A beta to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar A beta bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to A beta neurotoxicity suggested that AP neurotoxicity involves APP. Thus A beta toxicity may be mediated by the interaction of fibrillar AP with neuronal membrane proteins, notably APP. An A beta-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.