Complement and microglia mediate early synapse loss in Alzheimer mouse models
Authors: Beth Stevens
Soyon Hong
Cynthia A Lemere
Arnon Rosenthal
Bianca M Nfonoyim
Dennis J Selkoe
Victoria F Beja-Glasser
Shaomin Li
Qiaoqiao Shi
Katherine M Merry
Arnaud Frouin
Saranya Ramakrishnan
Ben A Barres
Journal: Science (2016)
Discipline: Multidisciplinary
Keywords: Synapse loss; Alzheimer's disease; microglia; complement; neuroinflammation
Affiliations: 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.

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 Œ≤-amyloid (AŒ≤) 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 AŒ≤ 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. 

Retracted: No

PubPeer comments:
 Some of the most important data in this paper is in Fig. 4D. It suggested that CR3 mediates microglia-mediated synapse engulfment. To determine whether inhibition in microglial engulfment leads to protection against Abeta-induced synapse loss, ***synthetic*** Abeta peptides were injected in the ***tail vein*** of mice. Remarkably, synthetic Abeta injected into the tail vein caused a reduction in colocalization of Synaptotagmin and Homer colocalization (a readout of synapse). Using ***only N=3*** mice per treatment group, this team managed to get extremely consistent synapse loss. This appears to be a quick Abeta toxicity assay if such data can be replicated. Q1) How much synthetic Abeta injected into tail vein actually got into the brain? Many others failed to detect any synthetic Abeta in the brain when Abeta was injected in the tail vein. Q2) Is there any rationale to inject 100 ng of synthetic Abeta in the tail vein? Is 100ng Abeta physiologically relevant? Q3) It is unclear why there is no error bar in PBS control groups. Q4) The number of microglia analyzed is a bit irrelevant because they should be averaged out for each mouse. Q5) If one compares between CR3 WT PBS group and CR3 KO PBS group, was there any difference in the number of synapses? Because data were presented as %PBS, it is not possible to compare these two groups. This is a critical question because the baseline data without Abeta treatment should be considered to properly interpret the data. Were there more synapses in CR3 KO PBS group compared to the CR3 WT PBS group? If so, the experimental design used by the author is invalid because the baseline is already different. ,