The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration

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. Description Nptx2 binds C1q and reduces complement activation and microglia-mediated synapse elimination in a tauopathy mouse model. A complementary role for Nptx2 Overactivation of the complement cascade has been implicated in neurodegenerative diseases such as frontotemporal dementia (FTD), although drivers of this overactivation have not been elucidated. Here, Zhou et al. identified the neuronal pentraxin Nptx2 as a regulator of complement C1q activity in the brain. The brains of mice lacking Nptx2 exhibited increased complement activity and increased synapse loss. In contrast, aged TauP301S mice, a mouse model of neurodegeneration, benefitted from adeno-associated virus-delivered Nptx2. These data, along with analysis of Nptx2 abundance in cerebrospinal fluid samples from patients with FTD, suggest that Nptx2 could be a therapeutic target for complement-associated neurodegenerative diseases. —CM

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