Endoplasmic Reticulum Stress Induces Tau Pathology and Forms a Vicious Cycle: Implication in Alzheimer's Disease Pathogenesis
Publication in refereed journal

香港中文大學研究人員

引用次數
替代計量分析
.

其它資訊
摘要Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2 alpha) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2 alpha, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration.
著者Ho YS, Yang XF, Lau JCF, Hung CHL, Wuwongse S, Zhang QS, Wang JZ, Baum L, So KF, Chang RCC
期刊名稱Journal of Alzheimer's Disease
出版年份2012
月份1
日期1
卷號28
期次4
出版社IOS PRESS
頁次839 - 854
國際標準期刊號1387-2877
電子國際標準期刊號1875-8908
語言英式英語
關鍵詞Alzheimer's disease; ER stress; okadaic acid; tau phosphorylation; thapsigargin
Web of Science 學科類別Neurosciences; NEUROSCIENCES; Neurosciences & Neurology

上次更新時間 2020-21-11 於 00:48