Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice.
10.3858/emm.2010.42.5.040
- Author:
Jin Hwan LEE
1
;
Sun Mi WON
;
Jaehong SUH
;
Sun Joo SON
;
Gyeong Joon MOON
;
Ui Jin PARK
;
Byoung Joo GWAG
Author Information
1. Department of Neuroscience, Ajou University School of Medicine, Suwon 442-749, Korea. bjgwag@ajou.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Alzheimer disease;
cell death;
endoplasmic reticulum;
protein disulfide-isomerases;
unfolded protein response
- From:Experimental & Molecular Medicine
2010;42(5):386-394
- CountryRepublic of Korea
- Language:English
-
Abstract:
The endoplasmic reticulum (ER) stress results from disrupted protein folding triggered by protein mutation or oxidation, reduced proteasome activity, and altered Ca2+ homeostasis. ER stress is accompanied by activation of the unfolded protein response (UPR) and cell death pathway. We examined if the UPR and cell death pathway would be activated in Alzheimer's disease (AD). RT-PCR experiments revealed increased splicing of X-box binding protein-1 (XBP-1), an UPR transcription factor, in AD compared with age-matched control. Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose-regulated protein 78 (GRP78), was increased in AD, suggesting disturbed activation of the UPR in AD. C/EBP homologous protein (CHOP), caspase-3, caspase-4, and caspase-12, downstream mediators of cell death pathway, were activated in AD. Neither the UPR nor cell death pathway was induced in aged Tg2576 mice, a transgenic mouse model of Alzheimer's disease that reveals both plaque pathology and some cognitive deficits. The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid beta and senile plaque.
