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

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.

Systematic proteomics in Autosomal dominant Alzheimer’s disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways

“…S1H). 69 In summary, this analysis revealed a significant degree of overlap between ADAD and sAD, while also validating the mutation carrier proteomic analyses in sAD and highlighted several proteins and potential mechanisms that are different between sAD and ADAD.…”

Normobaric hyperoxia alleviates complement C3‐mediated synaptic pruning and brain injury after intracerebral hemorrhage

“…When NBO therapy was used, the activation of C3 in microglia was suppressed, and the synaptic indices were restored, which ultimately lead to the mitigation of synaptic loss and neurological deficits in patients and animals. Notably, markedly increased expression levels of C3 and C3‐mediated synaptic elimination have been reported in multiple neurological disorders, such as AD, multiple sclerosis (MS), schizophrenia (SCZ), frontotemporal dementia (FTD) and otherneurodegenerative diseases 46–48 . Thus, our results revealed a previously unidentified role for C3‐mediated synaptic elimination in brain injury following hemorrhagic stroke.…”

“…Notably, markedly increased expression levels of C3 and C3-mediated synaptic elimination have been reported in multiple neurological disorders, such as AD, multiple sclerosis (MS), schizophrenia (SCZ), frontotemporal dementia (FTD) and otherneurodegenerative diseases. [46][47][48] Thus, our results revealed a previously unidentified role for C3-mediated synaptic elimination in brain injury following hemorrhagic stroke. NBO is a very common clinical adjuvant treatment, and the possiblemechanisms of NBO therapy include reducing blood occludin fragments, suppressing oxidative stress and improving mitochondrial function.…”

Heterogeneous complement and microglia activation mediates stress-induced synapse loss

“…Therefore, a straightforward mechanism for layer-specific complement activation is the stress-induced increase in the expression of complement components or activators in a particular neuronal or astrocytic layer 78 in the mPFC. Alternatively, a stress-induced decrease in the expression of complement inhibitors 46,79,80 within the upper layers can also lead to regional complement activation. In addition, inputs into the mPFC are known to be layer-specific 81 , and a stress-induced signals emanating from specific presynaptic terminals that are laminarly distributed may also trigger layer-specific complement and microglia activation.…”