MEF2C

Targeting part of an antiviral pathway triggered by the accumulation of a key pathogen shared in Alzheimer's disease and frontotemporal dementia may one day offer a new therapeutic approach to deterring or delaying cognitive decline, according to preclinical research led by Weill Cornell Medicine scientists. The study, published April 24 in Nature Neuroscience, demonstrates that inhibiting an innate immune system enzyme called cyclic GMP-AMP synthase (cGAS) helps neurons become resilient to the build-up of the protein tau into bundles known as fibrils, a hallmark of Alzheimers and some forms of frontotemporal dementia, the two most common dementias in the elderly population. "We are interested in this antiviral pathway because of its importance in modulating innate immunity - the bodys first line of defense against pathogens - which emerges as a major driver in neurodegenerative dementia," said the studys senior author, Dr. Li Gan, director of the Helen and Robert Appel Alzheimers Disease Research Institute and the Burton P. and the Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases at Weill Cornell Medicine. Dr. Gan and her colleagues studied immune cells of the nervous system called microglia. When microglia were exposed to abnormal tau, the mitochondria - or organelles that produce a cell's energy - leaked DNA into the cell fluid. This mitochondrial DNA leakage 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 get tricked into launching an antiviral response when there is actually no infection," Dr. Gan said. The 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 turn the switch on to instruct normal neuronal function, even in brains loaded with tau bundles." The researchers investigated the antiviral pathway by conducting laboratory studies in an Alzheimers disease mouse model. "These mice have abnormal tau accumulation in their brain and cognitive dysfunction that exacerbates with age," said one of the first co-authors of the paper Dr. Sadaf Amin, a postdoctoral associate in neuroscience in Gan lab at the Appel Alzheimer's Disease Research Institute at Weill Cornell Medicine. "Tau activates innate immune system and interferon signaling, which is switched off if we inhibit cGAS enzyme." The researchers used single-nuclei RNA sequencing to study gene expression in individual cells genome-wide. "We were able to evaluate changes at the single-cell level across the whole genome and pinpoint cross-talks between different cell types, meaning we could identify changes that occurred through genetic deletion of the antiviral pathway or with pharmacological inhibition," Dr. Gan said. Notably, removing the cGAS gene in these mice dampened the immune response of microglia and IFN-I. This preserved the function of synapses, or the communication junction between neurons and other cells, and protected against cognitive decline function regardless of the accumulation of abnormal tau protein. "Deleting the cGAS gene preserves the function of Mef2c that renders the neurons resilient to tau pathology by limiting the interferon signaling from microglia," said Yige Huang, another first coauthor of the paper and a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences in the Gan lab. The researchers were able to verify that these physiological mechanisms occur in humans using postmortem human tissue samples from Alzheimer's patients. In addition, the researchers discovered 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 hyperactive antiviral response, we may be able to harness the brains resilience program, postpone the disease onset, and extend normal cognition and quality of life in dementia patients," Dr. Gan said. Udeochu, J.C., Amin, S., Huang, Y. et al. Tau activation of microglial cGASIFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci, 2023. doi: 10.1038/s41593-023-01315-6

The key to a new cardiomyocyte-making technique is a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific. Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts. In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition. Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific. "It's an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming," said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine. Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly -- straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial ones. "Reprogramming fibroblasts has long been one of the important goals in the field," Qian said. "Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes." In the new study, Qian's team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells' gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings. Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer "transcription factor" proteins that had been used to make the neurons. Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming -- the proportion of successfully reprogrammed cells -- by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c. In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes. "Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail," Qian said. The results show that the major transcription factors used in direct cellular reprogramming aren't necessarily exclusive to one targeted cell type. Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them. "Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes" was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian. Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).