PMID- 37085004 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20230524 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 365 DP - 2023 Jul TI - Chaperone-mediated autophagy (CMA) alleviates cognitive impairment by reducing neuronal death in sepsis-associated encephalopathy (SAE). PG - 114417 LID - S0014-4886(23)00101-2 [pii] LID - 10.1016/j.expneurol.2023.114417 [doi] AB - Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis, which causes long-term neurological deficits, such as cognitive impairment. Despite extensive research, there is still lack of specific treatments for SAE. Chaperone-mediated autophagy (CMA), a selective type of autophagy, has been reported to be related to cognitive dysfunctions in many neurodegenerative diseases. The aim of this study was to investigate the alteration of CMA activity in the hippocampus of SAE mice and explore the neuroprotective effect of enhanced CMA. Cecal ligation and puncture (CLP) was conducted to induce SAE. In the contextual fear conditioning test, the ratio of freezing time of CLP mice significantly decreased compared with that of the mice in the Sham group, indicating cognitive impairment in SAE mice. The expression of lysosome-associated membrane protein type 2A (Lamp2a) and chaperone heat shock cognate 71 kDa protein (Hsc70), positive markers for CMA activity, decreased in hippocampal neurons of SAE mice. Although overexpression of Lamp2a in neurons via adeno-associated virus injection in the hippocampus had little effect on the mortality of septic mice, this intervention significantly alleviated the memory impairments in contextual fear conditioning test, Y-maze test and novel objective recognition test, and attenuated the neural death observed in SAE mice. We further demonstrated that the overexpression of Lamp2a in the hippocampus increased the expression of phosphorylated cyclic-AMP response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), and suppressed the expression of cleaved caspase-3. Taken together, our study results suggested that the upregulation of CMA activity ameliorated cognitive impairments and neuron loss in SAE mice partially through the p-CREB-BDNF/Bcl-2 signaling pathways, providing a potential therapeutic target for SAE. CI - Copyright (c) 2023. Published by Elsevier Inc. FAU - Li, Yi AU - Li Y AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Fan, Zhongmin AU - Fan Z AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Jia, Qi AU - Jia Q AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Ma, Hongwei AU - Ma H AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Wu, You AU - Wu Y AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Guo, Xiaofeng AU - Guo X AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Du, Lixia AU - Du L AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Wang, Xi AU - Wang X AD - Institute of Neurosciences, The Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Hou, Wugang AU - Hou W AD - Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Fang, Zongping AU - Fang Z AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: zongping03@163.com. FAU - Zhang, Xijing AU - Zhang X AD - Department of Critical Care Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: xjzhang0806@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230419 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Proto-Oncogene Proteins c-bcl-2) SB - IM MH - Mice MH - Animals MH - *Sepsis-Associated Encephalopathy MH - *Chaperone-Mediated Autophagy MH - Brain-Derived Neurotrophic Factor/metabolism MH - *Sepsis/complications MH - *Cognitive Dysfunction/etiology/metabolism MH - Autophagy MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Hippocampus/metabolism OTO - NOTNLM OT - Chaperone-mediated autophagy OT - Cognitive impairments OT - Neuronal death OT - P-CREB signaling pathways OT - Sepsis-associated encephalopathy COIS- Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/04/22 10:42 MHDA- 2023/05/22 06:42 CRDT- 2023/04/21 19:28 PHST- 2022/05/05 00:00 [received] PHST- 2023/03/29 00:00 [revised] PHST- 2023/04/17 00:00 [accepted] PHST- 2023/05/22 06:42 [medline] PHST- 2023/04/22 10:42 [pubmed] PHST- 2023/04/21 19:28 [entrez] AID - S0014-4886(23)00101-2 [pii] AID - 10.1016/j.expneurol.2023.114417 [doi] PST - ppublish SO - Exp Neurol. 2023 Jul;365:114417. doi: 10.1016/j.expneurol.2023.114417. Epub 2023 Apr 19.