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

研究成果: ジャーナルへの寄稿学術誌査読

16 被引用数 (Scopus)


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.

ジャーナルJournal of Alzheimer's Disease
出版ステータス出版済み - 2009

!!!All Science Journal Classification (ASJC) codes

  • 神経科学(全般)
  • 臨床心理学
  • 老年医学
  • 精神医学および精神衛生


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