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| PGC-1α as a potential therapeutic target for Alzheimer′s disease with a particular focus on OPA1 expression |
| LIU Wenjun1, SHI Houzhen1, ZHAI Hongru1, ZHANG Weijun1, #br# ZHU Yongqiang2, LIU Zizhong2, WANG Yuzhao3, WANG Jia 1,2 |
| (1. School of Medicine, Jiangsu University, Zhenjiang Jiangsu 212013; 2. Department of Neurology, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang Jiangsu 212001; 3. Department of Nursing, Binhai County People′s Hospital, Yancheng Jiangsu 224500, China ) |
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Abstract Objective： To explore the role of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in improving Alzheimer′s disease (AD), as well as its potential mechanisms with a particulars focus on optic atrophy 1 (OPA1) regulation. Methods： In vitro, AD models were constructed by transfecting APPswe plasmids into N2A cells. qRT-PCR was used to evaluate the impact of mutAPP overexpression on the varies of PGC-1α and OPA1 transcription. APPswe and PGC-1α plasmids were cotransfected into N2A cells, regulation effect of PGC-1α on the levels of OPA1 transcription were evaluated by qRT-PCR during AD. In vivo, by infusing AAV-PGC1α into the lateral parietal association (LPtA) cortex of APP/PS1 brain, we successfully overexpressed PGC-1α in the LPtA of APP/PS1 mouse. The regulatory effect of PGC1α on the expression of OPA1 and on the morphological changes of mitochondrial inner membrane during AD were examined by immunohistochemistry and transmission electron microscopy respectively. Results： Paralleling AD-like Aβ deposits, a significant reduction in the levels of PGC-1α and OPA1 was observed in APP/PS1 mice and APPswe transfected cells (all P<0.01). Furthermore, overexpression PGC-1a in LPtA rescued the mitochondrial damage, especially on damaged mitochondrial inner membrane in AD. Notably, upregulated expression of OPA1 were available in the LPtA cortex of APP/PS1 mice (all P<0.01) . Conclusion： PGC-1α contributes to the regulation of the mitochondrial fusion, thereby affecting Aβ aggregate in AD. Elevating of the PGC-1α level, either pharmacologically or through other means, could present a new therapeutic strategy for AD.
［Key words］Alzheimer′s disease; APP/PS1 mice; peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α); optic atrophy 1(OPA1); mitochondria; fusion protein
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Received: 02 April 2022
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