Synaptic failure underlies cognitive impairment in Alzheimer's disease (AD). Cumulative evidence suggests a strong link between mitochondrial dysfunction and synaptic deficits in AD. We previously found that oligomycin-sensitivity-conferring protein (OSCP) dysfunction produces pronounced neuronal mitochondrial defects in AD brains and a mouse model of AD pathology (5xFAD mice). Here, we prevented OSCP dysfunction by overexpressing OSCP in 5xFAD mouse neurons in vivo (Thy-1 OSCP/5xFAD mice). This approach protected OSCP expression and reduced interaction of amyloid-beta (Aβ) with membrane-bound OSCP. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aβ-mediated defects in axonal mitochondrial dynamics and motility. Consistent with preserved neuronal mitochondrial function, OSCP overexpression ameliorated synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density, reduced complement-dependent synapse elimination, and improved synaptic transmission, leading to preserved spatial learning and memory. Taken together, our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and implicate OSCP modulation as a potential therapeutic strategy.

中文翻译：

---

调节 OSCP 可减轻阿尔茨海默病小鼠模型中的线粒体和突触缺陷

突触衰竭是阿尔茨海默病 (AD) 认知障碍的基础。累积证据表明线粒体功能障碍与 AD 中的突触缺陷之间存在密切联系。我们之前发现寡霉素敏感性赋予蛋白 (OSCP) 功能障碍会在 AD 大脑和 AD 病理学小鼠模型（5xFAD 小鼠）中产生明显的神经元线粒体缺陷。在这里，我们通过在体内 5xFAD 小鼠神经元（Thy-1 OSCP/5xFAD 小鼠）中过度表达 OSCP 来预防 OSCP 功能障碍。这种方法保护了 OSCP 的表达并减少了淀粉样蛋白-β (Aβ) 与膜结合的 OSCP 的相互作用。OSCP 过表达还减轻了 F1Fo ATP 合酶的失调并保留了线粒体功能。此外，OSCP 调节赋予了对 Aβ 介导的轴突线粒体动力学和运动缺陷的抵抗力。与保留的神经元线粒体功能一致，OSCP 过表达改善了 5xFAD 小鼠的突触损伤，如保留的突触密度、减少补体依赖性突触消除和改善突触传递，从而保留空间学习和记忆。总之，我们的研究结果显示了 OSCP 功能障碍对 AD 相关疾病中突触应激发展的影响，并暗示 OSCP 调节是一种潜在的治疗策略。