Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China.
Department of Gerontology, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China.
Transl Psychiatry. 2022 Mar 8;12(1):96. doi: 10.1038/s41398-022-01862-9.
Soluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ. Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD.
可溶性淀粉样蛋白-β 蛋白（Aβ）寡聚体是 AD 的主要标志之一，通过多种病理学途径触发整合应激反应（ISR），包括神经元过度兴奋、微血管缺氧和神经炎症。增加 eIF2α 磷酸化是 ISR 的核心事件，促进代谢型谷氨酸受体（mGluR）依赖性长时程抑制（LTD），而抑制其磷酸化则有相反的效果。我们在活体大鼠中发现 Aβ 促进 mGluR5-LTD，因此想知道抑制 eIF2α 磷酸化级联是否会保护突触可塑性和认知破坏作用。我们在这里证明，单次脑室内注射合成 Aβ 在延迟大鼠模型中促进 mGluR5-LTD。ISR 的小分子抑制剂 ISRIB（反式异构体）的系统给药可防止 Aβ 促进的 LTD，并消除外源性合成 Aβ 注射大鼠海马中的空间学习和记忆缺陷。此外，离体证据表明 ISRIB 可使海马中的蛋白质合成正常化。通过用 eIF2B 激活剂 ISRIB 抑制 eIF2α 磷酸化级联来靶向 ISR，可能会提供针对 Aβ 的突触和认知破坏作用的保护作用，这可能介导散发性 AD 的早期阶段。
