Meng Peixin, Sha Longze, Yu Xiaolin, Wang Yanbing, Zhang Erning, Meng Kexin, Li Bingnan, Zhao Qin, Xu Qi
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
Neurosci Bull. 2025 Sep 5. doi: 10.1007/s12264-025-01492-3.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurotoxic amyloid beta (Aβ) deposition in the brain. Neurons can internalize and exocytose Aβ; however, the molecular pathways governing Aβ release remain poorly understood. To identify key regulators of Aβ42 transport, we applied formaldehyde cross-linking of protein complexes combined with co-immunoprecipitation and mass spectrometry analysis to identify TMED10 as a novel Aβ42-interacting protein. In cultured neurons, TMED10 knockdown (KD) increased intracellular Aβ42 levels by preventing Aβ42 exocytosis. TMED10 expression was significantly reduced in the cortex of AD patients. Overexpression of TMED10 in primary neurons mitigated the toxic effects of exogenous Aβ42. In 5 × FAD mice, overexpression of TMED10 via tail vein injection of a brain-penetrable adeno-associated virus improved cognitive function and reduced Aβ42 plaque accumulation. Together, these findings position TMED10 as a potential regulator of Aβ42 exocytosis and underscore the need for further studies to evaluate its therapeutic potential in AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中存在神经毒性淀粉样β蛋白（Aβ）沉积。神经元能够内化和胞吐Aβ；然而，调控Aβ释放的分子途径仍知之甚少。为了确定Aβ42转运的关键调节因子，我们应用蛋白质复合物甲醛交联结合免疫共沉淀和质谱分析，确定跨膜内质网蛋白10（TMED10）为一种新的与Aβ42相互作用的蛋白。在培养的神经元中，TMED10基因敲低（KD）通过阻止Aβ42胞吐作用增加细胞内Aβ42水平。AD患者皮质中TMED10表达显著降低。在原代神经元中过表达TMED10可减轻外源性Aβ42的毒性作用。在5×FAD小鼠中，通过尾静脉注射可穿透大脑的腺相关病毒过表达TMED10，改善了认知功能并减少了Aβ42斑块积累。总之，这些发现表明TMED10是Aβ42胞吐作用的潜在调节因子，并强调需要进一步研究以评估其在AD中的治疗潜力。
