Neuronal pentraxin Nptx2 regulates complement activity in the brain

Abstract

Complement overactivation mediates microglial synapse elimination in neurological diseases like Alzheimer 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.

Pituitary-immune bidirectional crosstalk under systemic inflammation

“…NPTX2 is a neuronal pentraxin, implicated in synaptic plasticity and excitatory synaptogenesis [6,7]. It has recently been shown that NPTX2 interacts with the complement protein C1q to restrict microglia complement-dependent synapse engulfment in neurodegeneration [8]. Despite the pentraxin superfamily being known for its evolutionarily conserved roles in innate immunity [9], the function of Nptx2 in the context of inflammation has not been studied.…”