2023-04-27 12:18:50
The study, published April 24 in Nature Neuroscience,
Inhibition of an innate immune system enzyme called cGAS (cyclic GMP-AMP synthase)
Neurons form bundles known as fibrils, a hallmark of Alzheimer’s disease.
Helps to be resilient to the accumulation of protein tau
(Sports People Times) = According to a preclinical study led by scientists at Cornell University, targeting parts of the antiviral pathway triggered by the accumulation of key pathogens shared by Alzheimer’s disease and frontotemporal dementia may one day inhibit cognitive decline or He said it might provide a new treatment that delays it.
The study, published April 24 in Nature Neuroscience, found that inhibiting an innate immune system enzyme called cGAS (cyclic GMP-AMP synthase) causes neurons to break into bundles known as fibrils that are characteristic of Alzheimer’s disease. show that the protein tau helps to become resilient to accumulation.
Forms of frontotemporal dementia, the two most common dementias in the elderly population.
“We are interested in this antiviral pathway because it is important for regulating innate immunity, the body’s first line of defense once morest pathogens that appear to be a major driver of neurodegenerative dementia. Robert Appel Alzheimer’s Institute, Burton P. and Judith B. Resnick Weill Distinguished Professor of Neurodegenerative Diseases Cornell Medicine.
Gan and her colleagues studied microglia, the immune cells of the nervous system. When microglia are exposed to abnormal tau, DNA leaks from mitochondria, organelles that produce cellular energy, into the cell fluid.
This mitochondrial DNA leak is recognized by the immune system as a viral invasion that activates cGAS. This enzyme then triggered sustained release of the immune system protein type I interferon (IFN-I).
“When bundles of tau proteins are loaded, they trick the brain into launching an antiviral response when there is actually no infection,” Gan said. Continuous IFN-I signaling from microglia reduced the activity of a protein called myocyte enhancer factor 2c (MEF2C). “By suppressing the antiviral response genetically or pharmacologically, we were able to flip a switch and direct normal neural function even in a brain full of tau bundles.”
The researchers investigated the antiviral pathway by conducting laboratory studies in a mouse model of Alzheimer’s disease. “These mice have abnormal accumulation of tau in their brains and cognitive impairment that worsens with age. Research lab at Weill Cornell Medicine. “Tau activates the innate immune system and interferon signaling, which is turned off by inhibiting the cGAS enzyme.”
The researchers studied gene expression in individual cells using single-nuclear RNA sequencing. “We were able to assess single-cell-level changes across the entire genome and pinpoint cross-talk between different cell types, i.e., changes caused by genetic deletion or pharmacological inhibition of the antiviral pathway. .” said Gan.
Specifically, deletion of the cGAS gene in these mice attenuated the immune response of microglia and IFN-I. This preserves the function of synapses, the junctions between neurons and other cells, and protects once morest cognitive decline independent of the accumulation of abnormal tau protein.
“Deleting the cGAS gene preserves Mef2c’s ability to make neurons resilient to tau pathology by limiting interferon signaling in microglia. Medical Sciences at the Gan Institute. Researchers used postmortem human tissue samples from Alzheimer’s patients to It was confirmed that these physiological mechanisms occur in humans.
Researchers also found that small-molecule cGAS inhibitors might restore MEF2C activity and improve memory function in mice with abnormal tau protein. Inhibitors also modulated antiviral pathways in human microglia derived from induced pluripotent stem cells.
“Further research is needed, but by suppressing the overactive antiviral response, we may be able to harness the brain’s resilience program, delay disease onset, and extend normal cognition and quality of life in people with dementia,” said Gan.
Many physicians and scientists at Weill Cornell Medicine maintain relationships and collaborate with external organizations to promote scientific innovation and provide expert guidance.
Go to Cornell University article
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