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Science DOI:10.1126/science.aad8373

Complement and microglia mediate early synapse loss in Alzheimer mouse models.

Publication TypeJournal Article
Year of Publication2016
AuthorsHong, S, Beja-Glasser, VF, Nfonoyim, BM, Frouin, A, Li, S, Ramakrishnan, S, Merry, KM, Shi, Q, Rosenthal, A, Barres, BA, Lemere, CA, Selkoe, DJ, Stevens, B
JournalScience
Volume352
Issue6286
Pages712-716
Date Published2016 May 06
ISSN1095-9203
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, CA1 Region, Hippocampal, Cognition Disorders, Complement C1q, Complement Pathway, Classical, Disease Models, Animal, Guanylate Kinases, Long-Term Potentiation, Macrophage-1 Antigen, Membrane Proteins, Mice, Mice, Knockout, Microglia, Phagocytosis, Plaque, Amyloid, Synapses, Synaptophysin, Up-Regulation
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.

URLhttp://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=27033548
DOI10.1126/science.aad8373
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27033548?dopt=Abstract

Alternate JournalScience
PubMed ID27033548
PubMed Central IDPMC5094372
Grant ListP01 AG015379 / AG / NIA NIH HHS / United States
R01NS083845 / NS / NINDS NIH HHS / United States
T32 AG000222 / AG / NIA NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
1RF1AG051496A / AG / NIA NIH HHS / United States
AG000222 / AG / NIA NIH HHS / United States
RF1 AG051496 / AG / NIA NIH HHS / United States
R01 NS083845 / NS / NINDS NIH HHS / United States