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Science. 2016 May 6;352(6286):712-716. doi: 10.1126/science.aad8373. Epub 2016 Mar 31.

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

Author information

F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
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.
Department of Neurobiology, Stanford University School of Medicine, Palo Alto, California 94305, USA.
Prothena Biosciences, Dublin, Ireland.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Contributed equally


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.

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