Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.
Yang Shi,Melissa Manis,Justin M. Long,Kairuo Wang,Patrick Sullivan,Javier Remolina Serrano,Rosa Hoyle,David M. Holtzman +7 more
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TLDR
It is found that microglia, instead of tau-induced direct neurotoxicity, are the driving force of neurodegeneration in a tauopathy mouse model and apoE strongly regulates neurodegenersation in the setting of tAUopathy predominantly by modulating microglial function.Abstract:
Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.read more
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Synergy between amyloid-β and tau in Alzheimer’s disease
TL;DR: Emerging evidence for an interaction between Aβ and tau during Alzheimer’s disease (AD) progression that challenges the classical linear trajectory model and offers a new perspective on AD pathophysiology and therapy is reviewed.
Journal ArticleDOI
APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches
TL;DR: Understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption, and it is important to use this body of knowledge to develop therapies directed at APOE.
Journal ArticleDOI
Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology.
Annerieke Sierksma,Ashley Lu,Renzo Mancuso,Nicola Fattorelli,Nicola Thrupp,Evgenia Salta,Jesus Zoco,David Blum,Luc Buée,Bart De Strooper,Bart De Strooper,Mark Fiers +11 more
TL;DR: It is concluded that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.
Journal ArticleDOI
Microglia: Agents of the CNS Pro-Inflammatory Response
José A. Rodríguez-Gómez,Edel Kavanagh,Pinelopi Engskog-Vlachos,Mikael K.R. Engskog,Antonio J. Herrera,Ana M. Espinosa-Oliva,Bertrand Joseph,Nabil Hajji,José L. Venero,Miguel Angel Burguillos +9 more
TL;DR: The phenotypic transformation from homeostatic microglia towards reactivemicroglia is discussed, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2) as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response.
Journal ArticleDOI
Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Sandro Da Mesquita,Sandro Da Mesquita,Zachary Papadopoulos,Taitea Dykstra,Logan Brase,Fabiana H.G. Farias,Morgan Wall,Hong Jiang,Chinnappa D. Kodira,Kalil Alves de Lima,Jasmin Herz,Antoine Louveau,Antoine Louveau,Dylan H. Goldman,Andrea Francesca Salvador,Suna Onengut-Gumuscu,Emily Farber,Nisha Dabhi,Tatiana Kennedy,Mary Grace Milam,Wendy Baker,Igor Smirnov,Igor Smirnov,Stephen S. Rich,Bruno A. Benitez,Celeste M. Karch,Richard J. Perrin,Martin R. Farlow,Jasmeer P. Chhatwal,David M. Holtzman,Carlos Cruchaga,Oscar Harari,Jonathan Kipnis +32 more
TL;DR: This paper showed that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits.
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The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases
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TL;DR: The TREM2-APOE pathway is identified 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.
Journal ArticleDOI
Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain
Monica R. P. Elmore,Allison R. Najafi,Maya A. Koike,Nabil N. Dagher,Elizabeth E. Spangenberg,Rachel A. Rice,Masashi Kitazawa,Bernice Matusow,Hoa Nguyen,Brian L. West,Kim N. Green +10 more
TL;DR: Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglian homeostasis in the adult brain are physiologically dependent upon CSF1R signaling.
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