Uric Acid Mitigates Cognitive Deficits via TFEB-Mediated Microglial Autophagy in Mice Models of Alzheimer's Disease

作者全名："Xiao, Qian; Wang, Jiaojiao; Tian, Qiuyun; Tian, Na; Tian, Qi; He, Xin; Wang, Yutian; Dong, Zhifang"

作者地址："[Xiao, Qian; Wang, Jiaojiao; Tian, Qiuyun; Tian, Na; He, Xin; Dong, Zhifang] Chongqing Med Univ, Pediat Res Inst,China Int Sci & Technol Cooperat B, Natl Clin Res Ctr Child Hlth & Disorders,Natl Clin, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China; [Tian, Qi] Chongqing Med Univ, Affiliated Hosp 1, Dept Geratol, Chongqing Key Lab Neurol, Chongqing, Peoples R China; [Wang, Yutian] Univ British Columbia, Brain Res Ctr, Vancouver, BC, Canada"

通信作者："Dong, ZF (通讯作者)，Chongqing Med Univ, Pediat Res Inst,China Int Sci & Technol Cooperat B, Natl Clin Res Ctr Child Hlth & Disorders,Natl Clin, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China."

来源：MOLECULAR NEUROBIOLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001121585100001

JCR分区：Q1

影响因子：5.1

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Uric acid; Autophagy; Transcription factor EB; Alzheimer's disease; Neuroprotection

摘要："Clinical trials have demonstrated the potential neuroprotective effects of uric acid (UA) in Alzheimer's disease (AD). However, the specific mechanism underlying the neuroprotective effect of UA remains unclear. In the present study, we investigated the neuroprotective effect and underlying mechanism of UA in AD mouse models. Various behavioral tests including an elevated plus maze, Barnes maze, and Morris water maze were conducted to evaluate the impact of UA on cognitive function in beta-amyloid (A beta) microinjection and APP23/PS45 double transgenic mice models of AD. Immunohistochemical staining was employed to visualize pathological changes in the brains of AD model mice. Western blotting and immunofluorescence techniques were used to assess levels of autophagy-related proteins and transcription factor EB (TFEB)-related signaling pathways. BV2 cells were used to investigate the association between UA and microglial autophagy. We reported that UA treatment significantly alleviated memory decline in A beta-induced AD model mice and APP23/PS45 double transgenic AD model mice. Furthermore, UA activated microglia and upregulated the autophagy-related proteins such as LC3II/I ratio, Beclin-1, and LAMP1 in the hippocampus of AD model mice. Similarly, UA protected BV2 cells from A beta toxicity by upregulating the expressions of Beclin-1, LAMP1, and the LC3II/I ratio, whereas genetic inhibition of TFEB completely abolished these protective effects. Our results indicate that UA may serve as a novel activator of TFEB to induce microglia autophagy and facilitate A beta degradation, thereby improving cognitive function in AD model mice. Therefore, these findings suggest that UA may be a novel therapeutic agent for AD treatment."

基金机构：National Natural Science Foundation of China

基金资助正文：No Statement Available