Alzheimer amyloid protein precursor complexes with brain GTP-binding protein Go

Abstract

THE most characteristic change in progressive dementia of Alzheimer's type is a tissue deposit of amyloid β/A4 protein1, which is derived from its precursor protein APP (ref. 2). Structural alterations of APP are implicated in the pathogenesis of Alzheimer's disease, but it is not known how they cause the disease. Although APP has a receptor-like architecture2–5, is located on the neuronal surface6, and has a conserved cytoplasmic domain7, no receptor function has been demonstrated for APP. Here we report that APP forms a complex with Go, a major GTP-binding protein in brain. The cytoplasmic APP sequence His 657–Lys 676 shows a specific Go-activating function and is necessary for complex formation. Go protein treated with GTP-γS lost the ability to associate with APP. This suggests that APP is a receptor coupled to Go and that abnormal APP–Go signalling is involved in the Alzheimer's disease process.