Dietary Salt Disrupts Tricarboxylic Acid Cycle and Induces Tau Hyperphosphorylation and Synapse Dysfunction during Aging

作者全名："Yuan, Minghao; Wang, Yangyang; Wen, Jie; Jing, Feng; Zou, Qian; Pu, Yinshuang; Pan, Tingyu; Cai, Zhiyou"

作者地址："[Yuan, Minghao; Jing, Feng; Cai, Zhiyou] Chongqing Med Univ, Chongqing, Peoples R China; [Yuan, Minghao; Jing, Feng; Cai, Zhiyou] Univ Chinese Acad Sci, Chongqing Sch, Dept Neurol, Chongqing, Peoples R China; [Yuan, Minghao; Wang, Yangyang; Jing, Feng; Zou, Qian; Pu, Yinshuang; Pan, Tingyu; Cai, Zhiyou] Chongqing Gen Hosp, Dept Neurol, Chongqing 400016, Peoples R China; [Yuan, Minghao; Wang, Yangyang; Jing, Feng; Zou, Qian; Pu, Yinshuang; Pan, Tingyu; Cai, Zhiyou] Chongqing Key Lab Neurodegenerat Dis, Chongqing, Peoples R China; [Wen, Jie] Guangdong Med Univ, Zhanjiang, Guangdong, Peoples R China"

通信作者："Cai, ZY (通讯作者)，Chongqing Gen Hosp, Dept Neurol, Chongqing 400016, Peoples R China."

来源：AGING AND DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000968796400018

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：13

期号：5

开始页：1532

结束页：1545

文献类型：Article

关键词：Dietary Salt; Tricarboxylic Acid Cycle; Tau Hyperphosphorylation; Synapse dysfunction; Cognitive Impairment

摘要："Dietary salt causes synaptic deficits and tau hyperphosphorylation, which are detrimental to cognitive function. However, the specific effects of a high-salt diet on synapse and tau protein remain poorly understood. In this study, aged (15-month-old) C57BL/6 mice received a normal (0.5% NaCl) or high-salt (8% NaCl) diet for 3 months, and N2a cells were treated with normal culture medium or a NaCl medium (40 mM). Spatial learning and memory abilities were tested using the Morris water maze. The levels of metabolites and related enzymes in the tricarboxylic acid (TCA) cycle were confirmed using liquid chromatography-tandem mass spectrometry, western blotting, and immunofluorescence. We also investigated synapse morphology and the phosphorylation of tau protein. Under the high-salt diet, mice displayed impaired learning and memory compared to mice fed the normal diet. Furthermore, excessive salt intake disturbed the TCA cycle in both animals and cells compared to the respective normal controls. High dietary salt reduced postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) expression, impaired neurons, and caused synaptic loss in the mice. We also detected tau hyperphosphorylation at different sites (Thr205, Thr231, and Thr181) without increasing total tau levels in response to high salt treatment, both in vivo and in vitro. We concluded that elevated salt intake impairs the TCA cycle and induces tau hyperphosphorylation and synapse dysfunction during aging, which ultimately results in cognitive impairment."

基金机构：Natural Science Foundation of Chongqing [cstc2021jcyj-bsh0154]; Provincial Nature Science Foundation of Anhui Province [1308085MH158]; National Institute of Neurological Disorders and Stroke; National Institutes of Health [R01NS079792]

基金资助正文："This work was supported by the Natural Science Foundation of Chongqing (cstc2021jcyj-bsh0154), the Provincial Nature Science Foundation of Anhui Province (1308085MH158 to Z.C.), and the National Institute of Neurological Disorders and Stroke, the National Institutes of Health (R01NS079792 to L.J.Y.). Zhiyou Cai and Minghao Yuan were responsible for the conception of the idea, data analysis, and manuscript preparation; Minghao Yuan, Yangyang Wang, Jie Wen, Feng Jing, Qian Zou and Yinshuang Pu performed the experimental work; Zhiyou Cai and Minghao Yuan prepared and revised the manuscript."