title: Complement and microglia mediate early synapse loss in Alzheimer mouse models.
abstract: Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Soyon
authors.initials: S
authors.lastname: Hong
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Victoria F
authors.initials: VF
authors.lastname: Beja-Glasser
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Nfonoyim
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Frouin
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Saranya
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Merry
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Qiaoqiao
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Alector Inc., 953 Indiana St, San Francisco, California 94107, USA.|Annexon Biosciences, 280 Utah Avenue Suite 110, South San Francisco, California 94080, USA.|Department of Anatomy, University of California San Francisco, California 94143, USA.
authors.forename: Arnon
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Palo Alto, California 94305, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
authors.affiliation: Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Prothena Biosciences, Dublin, Ireland.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000276:immunology / Q000473:pathology; D015922:Complement C1q / Q000235:genetics / Q000276:immunology*; D003171:Complement Pathway, Classical / Q000276:immunology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000276:immunology; D017774:Long-Term Potentiation; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D058225:Plaque, Amyloid / Q000276:immunology; D013569:Synapses / Q000276:immunology* / Q000473:pathology*; D016708:Synaptophysin / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D016708:Synaptophysin; D015922:Complement C1q; D051528:Guanylate Kinases