Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Synaptic dysfunction has appeared in the early stage of AD and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here we found upregulated Maf1 transcription factor in AD, and Maf1 conditional knockout in AD transgenic mice restored learning and memory function. Downregulation of Maf1 reduced intraneuronal Ca2+ concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodeling in neurons. Therefore, our results clarified the important role and mechanism of the Maf1-NMDAR1 signaling pathway in the stability of the synaptic structure, neuronal function, and behavior during the pathogenesis of AD, serving as a potential diagnostic and therapeutic target for the early onset of AD.

中文翻译：

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Maf1 缺失可调节脊柱生成并减轻阿尔茨海默病中的认知障碍

阿尔茨海默病（AD）是一种以进行性认知障碍为特征的神经退行性疾病。突触功能障碍在AD早期就已出现，且与认知障碍显着相关。但具体监管机制尚不清楚。在这里，我们发现 AD 中 Maf1 转录因子上调，并且 AD 转基因小鼠中 Maf1 条件性敲除恢复了学习和记忆功能。Maf1 的下调可降低神经元内 Ca2+ 浓度并恢复神经元突触形态。我们还证明，Maf1 通过与 Grin1 启动子区域结合来调节 NMDAR1 的表达，进一步调节神经元中的钙稳态和突触重塑。因此，我们的研究结果阐明了Maf1-NMDAR1信号通路在AD发病过程中突触结构、神经元功能和行为稳定性的重要作用和机制，为AD早期发病的潜在诊断和治疗靶点。