@article{ac905c18cf9d44bbac6797d895e6fdf7,
title = "The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases",
abstract = "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. Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases and suggest that targeting this pathway could restore homeostatic microglia.",
keywords = "APOE, Alzheimer's disease, TREM2, amyotrophic lateral sclerosis, microglia, multiple sclerosis, neurodegeneration, transcriptional regulation",
author = "Susanne Krasemann and Charlotte Madore and Ron Cialic and Caroline Baufeld and Narghes Calcagno and {El Fatimy}, Rachid and Lien Beckers and Elaine O'Loughlin and Yang Xu and Zain Fanek and Greco, {David J.} and Smith, {Scott T.} and George Tweet and Zachary Humulock and Tobias Zrzavy and Patricia Conde-Sanroman and Mar Gacias and Zhiping Weng and Hao Chen and Emily Tjon and Fargol Mazaheri and Kristin Hartmann and Asaf Madi and Ulrich, {Jason D.} and Markus Glatzel and Anna Worthmann and Joerg Heeren and Bogdan Budnik and Cynthia Lemere and Tsuneya Ikezu and Heppner, {Frank L.} and Vladimir Litvak and Holtzman, {David M.} and Hans Lassmann and Weiner, {Howard L.} and Jordi Ochando and Christian Haass and Oleg Butovsky",
note = "Funding Information: This work was supported by grants from the following organizations to the indicated authors. O.B.: NIH National Institute of Neurological Disorders and Stroke ( 1R01NS088137 ), NIH National Institute on Aging (NIH-NIA) ( R01AG051812 and R01AG054672 ), National Multiple Sclerosis Society ( 5092A1 ), Amyotrophic Lateral Sclerosis Association ( 2087 ), Nancy Davis Foundation Faculty Award, Cure Alzheimer{\textquoteright}s Fund ( 2017APOE :Butovsky). H.L.W.: Department of Defense ( AL120029 ), Thome Foundation ( 2011D002865 ), NIH-NIA ( R01AG043975 and R01AG040092 ). C.H.: European Research Council ( 321366-Amyloid ), Deutsche Forschungsgemeinschaft (DFG) ( EXC 1010 SyNergy ), Cure Alzheimer's Fund , MetLife Foundation Award . J.H.: DFG ( SFB841 ). D.M.H.: P50AG05681 , P01-AG0399 . C.L.: NIH-NIA ( R01AG040092 ). T.I.: NIH-NIA ( RF1AG054199-01 ). M.G.: DFG ( GRK1459 , SFB877 ). H.L.: Austrian Science Foundation Project ( P27744-B27 ). C.M.: National Multiple Sclerosis Society (postdoctoral fellowship). We thank Prize4Life, a nonprofit organization dedicated to the discovery of treatments and a cure for ALS; Marco Colonna for Trem2 −/− mice; Microscopy Core Facility/Universit{\"a}tsklinikum Hamburg-Eppendorf; Deneen Kozoriz for FACS sorting. C.H. is a Roche advisor and collaborator. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = sep,
day = "19",
doi = "10.1016/j.immuni.2017.08.008",
language = "English",
volume = "47",
pages = "566--581.e9",
journal = "Immunity",
issn = "1074-7613",
number = "3",
}