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 Aβreleas...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 Aβrelease 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.展开更多
基金supported by research grants from the National Key Research and Development Program of China(2020YFA0804502)the National Natural Science Foundation of China(82101545)+1 种基金the CAMS Innovation Fund for Medical Sciences(2022-I2M-1-002)National High-Level Hospital Clinical Research Funding(2022-PUMCH-D-002).
文摘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 Aβrelease 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.
