The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer’s disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.

中文翻译：

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中脑星形胶质细胞衍生的神经营养因子 （MANF） 表达增加导致阿尔茨海默病的突触丢失


内质网 （ER） 应激的激活是阿尔茨海默病 （AD） 大脑的早期病理标志，但 ER 应激如何导致 AD 的发生和发展仍然难以表征。中脑星形胶质细胞衍生的神经营养因子 （MANF） 是一种非经典神经营养因子，也是一种 ER 应激诱导蛋白。以前的研究报告说，症状前和症状性 AD 患者的大脑中 MANF 均增加，但 MANF 蛋白早期升高的后果尚不清楚。我们检查了不同病理阶段 AD 小鼠模型大脑中 MANF 的表达。通过行为、电生理和神经病理学分析，我们评估了在大脑中过表达 MANF 的 MANF 转基因小鼠模型和在海马中过表达 MANF 的野生型 （WT） 小鼠中的突触功能障碍水平。使用蛋白质组学和转录组学筛选，我们确定并验证了 MANF 对突触功能影响的分子机制。我们发现 MANF 表达的增加与 AD 小鼠海马体中的突触丢失相关。通过转基因或病毒途径在小鼠中异位表达 MANF 会导致突触丢失以及学习和记忆缺陷。我们还发现 MANF 与 RNA 结合蛋白 2 （ELAVL2） 一样与 ELAV 相互作用，并影响其与参与突触功能的 RNA 转录本的结合。AD 小鼠海马中 MANF 表达的增加或减少分别加剧或改善行为缺陷和突触病理。我们的研究将 MANF 确立为 AD 中 ER 应激与突触丢失之间的机制联系，并暗示 MANF 是 AD 治疗的治疗靶点。