TREM2-载脂蛋白E通路驱动神经退行性疾病中功能失调的小胶质细胞的转录表型。
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
作者信息
Krasemann Susanne, Madore Charlotte, Cialic Ron, Baufeld Caroline, Calcagno Narghes, El Fatimy Rachid, Beckers Lien, O'Loughlin Elaine, Xu Yang, Fanek Zain, Greco David J, Smith Scott T, Tweet George, Humulock Zachary, Zrzavy Tobias, Conde-Sanroman Patricia, Gacias Mar, Weng Zhiping, Chen Hao, Tjon Emily, Mazaheri Fargol, Hartmann Kristin, Madi Asaf, Ulrich Jason D, Glatzel Markus, Worthmann Anna, Heeren Joerg, Budnik Bogdan, Lemere Cynthia, Ikezu Tsuneya, Heppner Frank L, Litvak Vladimir, Holtzman David M, Lassmann Hans, Weiner Howard L, Ochando Jordi, Haass Christian, Butovsky Oleg
机构信息
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
Immunity. 2017 Sep 19;47(3):566-581.e9. doi: 10.1016/j.immuni.2017.08.008.
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
小胶质细胞在维持脑内稳态中起关键作用，但在神经退行性疾病期间会丧失稳态功能。我们在肌萎缩侧索硬化症（ALS）、多发性硬化症（MS）和阿尔茨海默病（AD）模型的小胶质细胞中，以及在AD患者大脑中围绕神经炎性β-淀粉样蛋白（Aβ）斑块的小胶质细胞中，鉴定出一种特定的载脂蛋白E（APOE）依赖性分子特征。在吞噬凋亡神经元后，APOE途径介导了小胶质细胞从稳态表型向神经退行性表型的转变。触发受体表达于髓样细胞2（TREM2）诱导APOE信号传导，靶向TREM2-APOE途径可恢复ALS和AD小鼠模型中小胶质细胞的稳态特征，并在急性神经退行性模型中防止神经元丢失。APOE介导的神经退行性小胶质细胞丧失了其免疫耐受功能。我们的研究确定TREM2-APOE途径是神经退行性疾病中小胶质细胞功能表型的主要调节因子，并作为一个新靶点，有助于恢复稳态小胶质细胞。
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