Study reveals a driver of brain cell damage in neurodegeneration

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"... A new study l... has identified the first known regulator of the complement system in the adult brain: the neuronal pentraxin protein Nptx2. Loss of Nptx2 leaves the cascade unchecked, exacerbating synapse destruction. In models of neurodegeneration, the researchers overcame these effects by boosting Nptx2 levels or blocking complement protein in cells, suggesting that therapeutic strategies targeting the complement system could prevent or even reverse damage to brain cells in neurodegenerative disease. ...
“This study contributes to the emerging picture of the complement cascade’s role across a range of neurological disorders,” ...

The scientists zeroed in on the pentraxin called Nptx2, which is secreted by excitatory neurons and is a biomarker for a range of neurological disorders. In patients with Alzheimer’s disease, frontotemporal dementia, schizophrenia, and Down’s syndrome, Nptx2 is depleted in the cerebrospinal fluid that surrounds the brain and spinal cord.

In their study, the researchers saw that Nptx2 directly and specifically binds and inhibits the activity of C1q, the initiating factor of the complement cascade.

Further, in an animal model lacking Nptx2, they found increased activity of the complement system along with destruction of synapses by microglia. When they eliminated C1q in these animals through genetic deletion or antibody blocking, synapses in the brain tissue recovered.

In an animal model of neurodegeneration marked by overactive microglia and elevated complement activity, boosting the production of Nptx2 in certain brain cells led to a decrease in complement activity and reversed the loss of synapses. ..."

From the 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."

Study reveals a driver of brain cell damage in neurodegeneration | Broad Institute Researchers identify a protein in the brain that regulates the complement cascade, which has been linked to Alzheimer’s disease and schizophrenia and is a possible drug target.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration (no public access)

A section of brain from a mouse model of neurodegeneration, showing a control protein in green, Nptx2 in red, and glial cells in white. Boosting Nptx2 rescued synapses and reduced complement overactivity.