Alzheimer's disease: a dysfunction of the amyloid precursor protein

In this review, we argue that at least one insult that causes Alzheimer's d isease (AD) is disruption of the normal function of the amyloid precursor p rotein (APP). Familial Alzheimer's disease (FAD) mutations in APP cause a d isease phenotype that is identical (with the exception that they cause an e arlier onset of the disease) to that of 'sporadic' AD. This suggests that t here are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 a nd overexpress APP several-fold in the brain. develop the pathology of AD i f they live past the age of 40. These data support the primacy of APP in th e disease. Although APP is the source of the beta -amyloid (A beta) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of A beta from this molecule. We suggest instead tha t APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cel l cycle abnormalities in the neuron, and that these abnormalities constitut e one mechanism of neuronal death in AD. Data supporting these hypotheses h ave come from investigations of the molecular consequences of neuronal expr ession of FAD mutants of APP or overexpression of wild type APP. as well as from identification of binding proteins for the carboxyl-terminus (C-termi nus) of APP. (C) 2000 Elsevier Science B.V. All rights reserved.