Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors

Linqing Ma, Yasumasa Ohyagi, Katsue Miyoshi, Nobutaka Sakae, Kyoko Motomura, Takayuki Taniwaki, Hirokazu Furuya, Kazuya Takeda, Takeshi Tabira, Jun Ichi Kira

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-β-{42} (Aβ-{42}) production as well as to promote apoptosis. We have recently reported that intracellular Aβ-{42} activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a β-secretase inhibitor and γ-secretase inhibitor decreased the intracellular Aβ levels in amyloid-β protein precursor (AβPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AβPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Aβ and proteasome impairment.

Original languageEnglish
Pages (from-to)565-575
Number of pages11
JournalJournal of Alzheimer's Disease
Volume16
Issue number3
DOIs
Publication statusPublished - 2009

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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