The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration
Name
2022.09.22.509106v1.full.pdf
Description
Submitted version
Size
7.75 MB
Format
Adobe PDF
Checksum (MD5)
d7f87097e46b2bdfc91c9508c0df76fe
Author(s)
Zhou, Jiechao
Wade, Sarah D
Graykowski, David
Xiao, Mei-Fang
Zhao, Binhui
Giannini, Lucia AA
Hanson, Jesse E
van Swieten, John C
Sheng, Morgan
Worley, Paul F
Date Issued
March 29, 2023
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Zhou, Jiechao, Wade, Sarah D, Graykowski, David, Xiao, Mei-Fang, Zhao, Binhui et al. 2023. "The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration." Science Translational Medicine, 15 (689).
Version
Original manuscript
Abstract
Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)–mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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DOI of Published Version
https://doi.org/10.1126/scitranslmed.adf0141
