The antiviral pathway, a new potential target for the treatment of Alzheimer’s disease

Summary: By inhibiting cGAS, an enzyme of the innate immune system, neurons become more resistant to tau fibrils. The new finding could be used to develop new therapies to help treat Alzheimer’s disease and frontotemporal dementia, two neurodegenerative disorders associated with tau buildup in the brain.

Source: Weill Cornell University

Targeting part of an antiviral pathway triggered by the accumulation of a key pathogen common to Alzheimer’s disease and frontotemporal dementia could one day offer a new therapeutic approach to deterring or delaying cognitive decline, research suggests preclinical study conducted by scientists at Weill Cornell Medicine.

The study, published April 24 in Natural neurosciencedemonstrates that inhibiting an innate immune system enzyme called cyclic GMP-AMP synthase (cGAS) helps neurons become resistant to the accumulation of tau protein in bundles called fibrils, a hallmark of Alzheimer’s disease and certain forms of frontotemporal dementia, the two most common dementias in the elderly.

“We are interested in this antiviral pathway because of its importance in modulating innate immunity – the body’s first line of defense against pathogens – which appears to be a major driver of neurodegenerative dementia,” said the study’s lead author, Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and the Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases at Weill Cornell Medicine.

Dr. Gan and his colleagues studied nervous system immune cells called microglia. When microglia were exposed to an abnormal tau protein, the mitochondria, or organelles that produce a cell’s energy, leaked DNA into the cellular fluid.

This leak of mitochondrial DNA was perceived by the immune system as a viral invasion, activating cGAS. This enzyme then triggered the sustained release of the immune system protein type I interferon (IFN-I).

“When loaded with tau protein bundles, brains are tricked into launching an antiviral response when there is actually no infection,” Dr. Gan said.

Sustained IFN-I signaling from microglia decreased the activity of a protein called myocyte enhancer factor 2c (MEF2C), which is a molecular switch that provides neurons with the blueprint to function normally and resist cognitive decline.

“By inhibiting the antiviral response both genetically and pharmacologically, we were able to flip the switch to instruct normal neuronal function, even in brains loaded with tau bundles.”

The researchers studied 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 dysfunction that worsens with age,” said one of the paper’s first co-authors, Dr. Sadaf Amin, postdoctoral associate in neuroscience. at the Gan laboratory of the Appel Alzheimer’s Disease Research Institute. at Weill Cornell Medicine.

“Tau activates the innate immune system and interferon signaling, which is turned off if we inhibit the cGAS enzyme.”

The researchers used single-nucleus RNA sequencing to study gene expression in individual cells at the genome-wide scale. “We were able to assess changes at the single cell level across the entire genome and identify cross-interactions between different cell types, meaning we were able to identify changes that occurred by genetic deletion of the antiviral pathway or by pharmacological inhibition,” Dr. Gan said. said.

Notably, deletion of the cGAS gene in these mice attenuated the microglia and IFN-I immune response. This preserved the function of synapses, or the communication junction between neurons and other cells, and protected against cognitive decline, independent of abnormal tau protein accumulation.

“Deletion of the cGAS gene preserves the function of Mef2c which renders neurons resistant to tau pathology by limiting interferon signaling from microglia,” said Yige Huang, another first co-author of the paper and a PhD student. at the Weill Cornell Graduate School of Medical Sciences. at the Gan laboratory.

The researchers were able to verify that these physiological mechanisms occur in humans using post-mortem human tissue samples from patients with Alzheimer’s disease.

Additionally, the researchers found that a small molecule cGAS inhibitor could restore MEF2C activity and improve memory function in mice with abnormal tau proteins. The inhibitor also modulated the antiviral pathway in human microglia derived from induced pluripotent stem cells.

“While further studies are needed, by suppressing the overactive antiviral response, we may be able to harness the brain’s resilience program, delay the onset of disease, and prolong normal cognition and quality of life in affected patients. dementia,” Dr. Gan said.

About this Alzheimer’s disease research news

Author: Barbara Prempeh
Source: Weill Cornell Medicine
Contact: Barbara Prempeh – Weill Cornell Medicine
Picture: Image is in public domain

Original research: Free access.
“Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience” by Li Gan et al. Natural neuroscience

Abstract

Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience

The pathological features of Alzheimer’s disease (AD) precede clinical symptoms by several years, indicating a period of cognitive resilience before the onset of dementia.

Here, we report that activation of cyclic GMP-AMP synthase (cGAS) decreases cognitive resilience by downregulating the transcriptional neural network of myocyte enhancing factor 2c (MEF2C) through type I interferon (IFN) signaling. -I).

Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgaz in mice with tauopathy decreased microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting pathogen tau load. Ablation of cGAS increased, while activation of IFN-I decreased, the neural expression network of MEF2C linked to cognitive resilience in AD.

Pharmacological inhibition of cGAS in mice with tauopathy enhanced the MEF2C neuronal transcriptional network and restored synaptic integrity, plasticity, and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve the resilience against AD-related pathological insults.