High-fat diet induces cognitive impairment through repression of SIRT1/ AMPK-mediated autophagy

作者全名："Yi, Wenmin; Chen, Fei; Yuan, Minghao; Wang, Chuanling; Wang, Shengyuan; Wen, Jie; Zou, Qian; Pu, Yinshuang; Cai, Zhiyou"

作者地址："[Yi, Wenmin] Chongqing Med Univ, Clin Coll 5, Chongqing 402160, Peoples R China; [Yi, Wenmin; Chen, Fei; Yuan, Minghao; Wang, Shengyuan; Wen, Jie; Zou, Qian; Pu, Yinshuang; Cai, Zhiyou] Chongqing Gen Hosp, Dept Neurol, Chongqing 400013, Peoples R China; [Yi, Wenmin; Chen, Fei; Yuan, Minghao; Wang, Chuanling; Wang, Shengyuan; Wen, Jie; Zou, Qian; Pu, Yinshuang; Cai, Zhiyou] Chongqing Key Lab Neurodegenerat Dis, Chongqing 400013, Peoples R China; [Yi, Wenmin; Chen, Fei; Yuan, Minghao; Wang, Chuanling; Wang, Shengyuan; Cai, Zhiyou] Chongqing Med Univ, Chongqing 400016, Peoples R China; [Yi, Wenmin; Chen, Fei; Yuan, Minghao; Wang, Shengyuan; Cai, Zhiyou] Univ Chinese Acad Sci, Chongqing Sch, Chongqing 400799, Peoples R China"

通信作者："Cai, ZY (通讯作者)，Chongqing Gen Hosp, Dept Neurol, Chongqing 400013, Peoples R China."

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001111012600001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：371

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：High-fat diet; SIRT1/AMPK; Autophagy; Cognitive impairment

摘要："Aims: Recent evidence suggests an association between a high-fat diet (HFD) and cognitive decline. HFD may reduce synaptic plasticity and cause tau hyperphosphorylation, but the mechanisms involved remain unclear. The purpose of this study was to explore whether Sirtuin1 (SIRT1)/AMP-activated protein kinase (AMPK) pathway was involved in this pathogenic effect in the HFD exposed mice. Methods: C57BL/6 mice at 12 months of age were fed a standard (9% kcal fat) or high-fat (60% kcal fat) diet for 22 weeks, and Neuro-2a (N2a) cells were treated with normal culture medium or a palmitic acid (PA) medium (100uM) for 40 h. After that, cognitive function was tested by Morris water maze (MWM). The levels of proteins involved in SIRT1/AMPK pathway and autophagy were measured using western blotting and immunofluorescence. We also assessed the phosphorylation of tau protein and synapse.Results: The mice presented impaired learning and memory abilities. We further found decreased levels of synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF), increased tau46 and phosphorylated tau protein, and damaged neurons in mice after HFD or in N2a cells treated with PA medium. Moreover, HFD can also reduce the expression of SIRT1, inhibit AMPK phosphorylation, and block autophagic flow in both mice and cells. After treating the cells with the SIRT1 agonist SRT1720, SIRT1/AMPK pathway and autophagy-related proteins were partially reversed and the number of PA-induced positive cells was alleviated in senescenceassociated beta-galactosidase (SA-beta-gal) staining.Conclusions: HFD may inhibit the expression of SIRT1/AMPK pathway and disrupt autophagy flux, and result in tau hyperphosphorylation and synaptic dysfunction during aging, which ultimately lead to cognitive decline."

基金机构："Construction Project of Capacity Improvement Plan for Chongqing Municipal Health Commission [(2019NLTS001) -ZS03174, 1000013]; Construction Project of Capacity Improvement Plan for Chongqing Municipal Health Commission affiliated unit [(2019NLTS001) -ZS03174]; Chongqing Key Laboratory of Neurodegenerative Diseases [1000013]; Chongqing Talent Project [2000062]; Overseas Students entrepreneurial fund [2000079]; Plan for High-level Talent Introduction [2000055]; Chongqing Postdoctoral Science Foundation [CSTB2022NSCQ-BHX0634]"

基金资助正文："This work was supported by the Construction Project of Capacity Improvement Plan for Chongqing Municipal Health Commission affiliated unit (2019NLTS001) -ZS03174, operating grant to Chongqing Key Laboratory of Neurodegenerative Diseases (1000013) , Chongqing Talent Project (2000062) , Overseas Students entrepreneurial fund (2000079) , Plan for High-level Talent Introduction (2000055) and Chongqing Postdoctoral Science Foundation (CSTB2022NSCQ-BHX0634) ."