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22 June 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.
Reference:Xiao Xu, Daseng Yang, Tony Wyss-Coray, Jim Yan, Li Gan, Yi Sun, and Lennart Mucke. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. PNAS 1999 June 22;(96):7547-7552. Abstract
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Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis.
