22 Jun 1999

Neurons taken from the brains of deceased Alzheimer's patients exhibit markers for apoptosis, but little is known about what induces the expression of apoptotic genes. In today’s proceedings of the National Academy of Science, a University of California, San Francisco, team led by Xiao Xu and Lennart Mucke report a novel interaction linking amyloid precursor protein (APP) to p53, a key gene regulating apoptosis. The researchers transfected APP-deficient rat neuroblastoma cells with DNA constructs encoding wild-type and FAD-mutant human APP, and found that those containing wild-type APP were protected against p53-induced apoptosis, whereas the mutant APP-containing cells were not. In addition, wildtype APP strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, but mutant APP did not. The researchers conclude that APP protects neuronal cells against apoptosis by controlling p53 activation, and that APP mutations may disrupt this function and leave neurons more vulnerable to insults.

“The inability of mutant APP to control p53 activation may help to explain, at least in part, why Alzheimer’s-linked APP mutations result in the early onset of neurodegenerative disease,” Mucke said. “The next step will be to determine if the APP mutations directly impair the protective function of APP or rather counteract it by increasing a neurotoxic APP breakdown product.”—Hakon Heimer