血管性认知障碍（VCI）是一种由脑血管问题和相关危险因素引起的临床综合征，导致至少一个认知功能领域出现困难。 VCI 已成为继阿尔茨海默病之后第二常见的痴呆类型，但尚无有效的临床治疗方法。 Botch 是一种内源性 Notch1 拮抗剂，通过抑制 Notch 通路介导的神经炎症反应来发挥神经保护作用。虽然它在中风引起的神经炎症中的作用已得到充分证实，但它在 VCI 中的作用仍然很大程度上未被探索。本研究探讨了 Botch 在双侧颈总动脉闭塞 (BCCAO) 引起的认知障碍大鼠模型中的作用和潜在机制。首先，我们观察到 BCCAO 大鼠中 Botch 水平下调，这与炎症细胞因子释放增加和神经元损伤相关。 BCCAO 大鼠的小胶质细胞释放白介素 1α (IL-1α)、肿瘤坏死因子 α (TNF-α) 和补体成分 1q (C1q)，导致神经毒性 C3 A1 反应性星形胶质细胞激活。然后，Botch 的下调加剧了小胶质细胞介导的炎症，激活了 C3 A1 星形胶质细胞，加剧了神经元损伤，并导致认知功能下降。相反，Botch 的重新表达减轻了 C3 星形胶质细胞的激活，抑制了神经元损伤，并改善了精神功能。总之，Botch 在抑制 A1 型反应性星形胶质细胞诱导的神经炎症方面发挥着至关重要的作用。它通过阻断 Notch 通路触发的小胶质细胞的激活来实现这一目标。最终，它抑制神经元损伤，发挥神经保护作用。这些发现表明 Botch 可能代表治疗 VCI 的新的潜在靶点。版权所有 © 2024。由 Elsevier Inc. 出版。

Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.Copyright © 2024. Published by Elsevier Inc.