Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models
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s43587-022-00281-1.pdf
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Published version
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20.16 MB
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Author(s)
Dejanovic, Borislav
Wu, Tiffany
Tsai, Ming-Chi
Graykowski, David
Gandham, Vineela D
Rose, Christopher M
Bakalarski, Corey E
Ngu, Hai
Wang, Yuanyuan
Pandey, Shristi
Date Issued
2022
Journal
Nature Aging
Publisher
Springer Science and Business Media LLC
Citation
Dejanovic, Borislav, Wu, Tiffany, Tsai, Ming-Chi, Graykowski, David, Gandham, Vineela D et al. 2022. "Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models." Nature Aging, 2 (9).
Version
Final published version
Abstract
AbstractMicroglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S43587-022-00281-1
