KMID : 0620920100420050386
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Experimental & Molecular Medicine 2010 Volume.42 No. 5 p.386 ~ p.394
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Induction of the unfolded protein response and cell death pathway in Alzheimer¡¯s disease, but not in aged Tg2576 mice
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Lee Jin-Hwan
Won Sun-Mi Suh Jae-Hong Son Sun-Joo Moon Gyeong-Joon Park Ui-Jin Gwag Byoung-Joo
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Abstract
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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 ¥â and senile plaque.
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KEYWORD
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Alzheimer disease, cell death, endoplasmic reticulum, protein disulfide-isomerases, unfolded protein response
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