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P2‐170: Activated PKR levels correlates with PACT levels in the brains of AD patients and in APP/PS1 KI transgenic mice
Author(s) -
Paquet Claire,
Mouton Liger François,
Bouras Constantin,
Vigny Marc,
Gray Françoise,
Hugon Jacques
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.482
Subject(s) - protein kinase r , genetically modified mouse , autophosphorylation , western blot , cyclin dependent kinase 5 , senile plaques , transgene , protein kinase a , kinase , biology , medicine , endocrinology , chemistry , microbiology and biotechnology , alzheimer's disease , cyclin dependent kinase 2 , biochemistry , disease , gene
simultaneous elevation of I2 , p53 and Akt was also observed in AD brain and the tg-2576 transgenic mice, suggesting an intrinsic link of I2 PP2A with p53 and Akt in AD. Further studies showed that I2 PP-2A protein could bind to the promoter regions of p53 and Akt and thus increase the transcription activity. Overexpression of I2 PP-2A could activate p53 through stimulating p38 MAPK but not Cdk5; however, the I2 -induced activation of p53 did not induce cell apoptosis for I2 PP-2A also activated Akt. Inhibition of Akt while overexpressing I2 PP-2A caused more severe apoptosis than that with Akt inhibition only. Knockdown p53 remarkably restored the decreased cell viability induced by simultaneous Akt inhibition and I2 PP-2A overexpression. Conclusions: These data suggest that I2 PP-2A can upregulate p53 and Akt by regulating the transcription activity and/or the p38 MAPK pathway. In addition, simultaneous activation of Akt counteracts the activated p53-induce apoptosis. Consistent with our recent report (Li et al., PNAS, 2007; 104: 3591-6), our findings uncover a new mechanism explaining why neurons in AD brain do not die preferentially of apoptosis even though exposed to a proapoptotic environment.