Neuronal pentraxin Nptx2 regulates complement activity in the brain

Complement overactivation mediates microglial synapse elimination in neurological diseases like Alzheimer’s disease 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 and C1q-dependent microglial synapse engulfment and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, AAV-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human CSF samples from a genetic FTD cohort revealed significantly reduced levels 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 healthy and diseased brain and that diminished Nptx2 levels might exacerbate complement-mediated neurodegeneration in FTD patients. ### Competing Interest Statement M.S. is scientific co-founder and member of the SAB of Neumora Therapeutics, and member of the SAB of Biogen, Vanqua Bio, ArcLight Therapeutics, Cerevel Therapeutics. P.F.W. is co-founder of CogNext. J.H. is employed by Genentech. The other authors declare no competing interests.