Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis

Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abund ance in brain and the association of various APP missense mutations with au tosomal dominant forms of familial Alzheimer's disease (FAD) suggest import ant roles for APP in the central nervous system, However, the basic functio ns of APP in the central nervous system remain largely unknown. To assess p otential effects of APP on neuronal death and survival, we transfected APP- deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild- type or FAD-mutant human APP, Wild-type, but not FAD-mutant, APP effectivel y protected cells against apoptosis induced by ultraviolet irradiation, sta urosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding a ctivity and p53-mediated gene transactivation, whereas FAD-mutant APP did n ot. We conclude that APP protects neuronal cells against apoptosis by contr olling p53 activation at the post-translational level. Disruption of this f unction by mutations or alterations in APP processing could enhance neurona l vulnerability to secondary insults and contribute to neuronal degeneratio n.