Alzheimer’s disease (AD) is the most common form of neurodegenerative disease featured with memory loss and cognitive function impairments. Chronic mitochondrial stress is a vital pathogenic factor for AD and finally leads to massive neuronal death. However, the underlying mechanism is unclear. By proteomic analysis, we identified a new mitochondrial protein, cell-cycle exit and neuronal differentiation 1 (CEND1), which was decreased significantly in the brain of 5xFAD mice. CEND1 is a neuronal specific protein and locates in the presynaptic mitochondria. Depletion of CEND1 leads to increased mitochondrial fission mediated by upregulation of dynamin related protein 1 (Drp1), resulting in abnormal mitochondrial functions. CEND1 deficiency leads to cognitive impairments in mice. Overexpression of CEND1 in the hippocampus of 5xFAD mice rescued cognitive deficits. Moreover, we identified that CDK5/p25 interacted with and phosphorylated CEND1 which promoted its degradation. Our study provides new mechanistic insights in mitochondrial function regulations by CEND1 in Alzheimer’s disease.

阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是记忆丧失和认知功能障碍。慢性线粒体应激是AD的重要致病因素，最终导致大量神经元死亡。然而，其根本机制尚不清楚。通过蛋白质组学分析，我们鉴定了一种新的线粒体蛋白，即细胞周期退出和神经元分化 1 (CEND1)，该蛋白在 5xFAD 小鼠的大脑中显着下降。 CEND1 是一种神经元特异性蛋白，位于突触前线粒体中。 CEND1 的缺失会导致动力相关蛋白 1 (Drp1) 上调介导的线粒体分裂增加，从而导致线粒体功能异常。 CEND1 缺陷会导致小鼠认知障碍。 5xFAD 小鼠海马体中 CEND1 的过度表达可挽救认知缺陷。此外，我们发现 CDK5/p25 与 CEND1 相互作用并磷酸化，从而促进其降解。我们的研究为阿尔茨海默病中 CEND1 调节线粒体功能提供了新的机制见解。