To much clining up

Complement and microglia mediate early synapse loss in Alzheimer mouse models

1. Soyon Hong1, 
2. Victoria F. Beja-Glasser1,*, 
3. Bianca M. Nfonoyim1,*, 
4. Arnaud Frouin1, 
5. Shaomin Li2, 
6. Saranya Ramakrishnan1, 
7. Katherine M. Merry1, 
8. Qiaoqiao Shi2, 
9. Arnon Rosenthal3,4,5, 
10. Ben A. Barres6, 
11. Cynthia A. Lemere2, 
12. Dennis J. Selkoe2,7, 
13. Beth Stevens1,8,†

+ Author Affiliations

1. ↵†Corresponding author. E-mail: beth.stevens@childrens.harvard.edu

1. ↵* These authors contributed equally to this work.

Science  06 May 2016:
Vol. 352, Issue 6286, pp. 712-716
DOI: 10.1126/science.aad8373

• Article
• Figures & Data
• Info & Metrics
• eLetters
•  PDF

You are currently viewing the abstract.

View Full Text

Too much cleaning up

The complement system and microglia seek out and destroy unwanted cellular debris for the peripheral immune system as well as excess synapses in the developing brain. Hong et al. now show how the system may go haywire in adults early in the progression toward Alzheimer's disease (AD). Aberrant synapse loss is an early feature of Alzheimer's and correlates with cognitive decline. In mice susceptible to AD, complement was associated with synapses, and microglial function was required for synapse loss. The authors speculate that aberrant activation of this “trash disposal” system underlies AD pathology.

Science, this issue p. 712

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.