Peixin Meng1  · Longze Sha1,2 · Xiaolin Yu1  · Yanbing Wang1  · Erning Zhang1  · Kexin Meng1  · Bingnan Li1,2 · Qin Zhao3  · Qi Xu1,2

1 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 

2 Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China 

3 College of Life Sciences, Beijing Normal University, Beijing 100875, China

Abstract

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.

Keywords

Alzheimer’s disease; Amyloid beta; Neuron; Exocytosis; TMED10

[SpringerLink]