脓毒症相关脑病（SAE）是脓毒症的常见且严重的并发症之一，会引起长期的神经系统缺陷，如认知损伤。尽管进行了广泛的研究，但仍缺乏治疗SAE的特定方法。伴随细胞自噬（CMA）是自噬的一种选择性类型，已被报道与许多神经退行性疾病中的认知功能障碍相关。本研究旨在调查SAE小鼠海马中CMA活性的变化，并探索增强CMA的神经保护作用。采用盲肠结扎穿孔（CLP）诱导SAE。在情境恐惧条件反射测试中，CLP小鼠的冻结时间比Sham组小鼠显著降低，表明SAE小鼠存在认知障碍。SAE小鼠海马神经元中的溶酶体相关膜蛋白2A（Lamp2a）和分子伴侣热休克型同源物71kDa蛋白（Hsc70），是CMA活性的阳性标志物，其表达下降。虽然通过腺相关病毒注射方式在海马神经元中过表达Lamp2a对脓毒症小鼠的生存率影响很小，但该干预措施显著缓解了情境恐惧条件反射测试、Y迷宫测试和新物体识别测试中的记忆障碍，并减轻了SAE小鼠中观察到的神经死亡。我们进一步证明，在海马中过表达Lamp2a增加了磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）、脑源性神经营养因子（BDNF）和B细胞淋巴瘤-2（Bcl-2）的表达，并抑制了cleaved caspase-3的表达。综上所述，我们的研究结果表明，上调CMA活性通过p-CREB-BDNF/Bcl-2信号转导途径部分缓解了SAE小鼠的认知障碍和神经元死亡，为SAE提供了潜在的治疗靶点。版权所有©2023 Elsevier Inc.

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.Copyright © 2023. Published by Elsevier Inc.