-Amyloid to the p75 Neurotrophin Receptor Induces Apoptosis A Possible Mechanism for Alzheimer’s Disease

Alzheimer’s disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of aggregated b -amyloid peptide, presumed to play a pathogenic role, and by preferential loss of neurons that express the 75-kD neurotrophin receptor (p75 NTR ). Using rat cortical neurons and NIH-3T3 cell line engineered to stably express p75 NTR , we find that the b -amyloid peptide specifically binds the p75 NTR . Furthermore, 3T3 cells expressing p75 NTR , but not wild-type control cells lacking the receptor, undergo apoptosis in the presence of aggregated b -amyloid. Normal neural crest–derived melanocytes that express physiologic levels of p75 NTR undergo apoptosis in the presence of aggregated b -amyloid, but not in the presence of control peptide synthesized in reverse. These data imply that neuronal death in Alzheimer’s disease is mediated, at least in part, by the interaction of b -amyloid with p75 NTR , and suggest new targets for therapeutic intervention. ( J. Clin. Invest. 1997. 100:2333–2340.)