Molecular Reprogramming of Microglia in Neurodegeneration

Microglia, the brain's primary immune cells, play various roles in Alzheimer's Disease (AD) with protective and neurodegenerative outcomes. Our lab recently identified a neurodegenerative subset of microglia characterized by the activation of the integrated stress response (ISR), a cellular stress response pathway. Notably, genetic and environmental AD risk factors, including the strongest genetic risk factor, APOE4, can activate ISR in microglia. We found that repeated microglial ISR activation, mimicking chronic exposure to these risk factors, worsens AD-related pathologies, while its inhibition mitigates these effects. These results suggest that ISR (induced by AD risk factors) could reprogram microglia toward a neurodegenerative state. However, whether and how repeated ISR activation can reprogram microglia remains unclear. A primary mechanism that mediates long-term cellular reprogramming is epigenetics, which involves the modification of DNA and DNA-bound histone proteins. In elucidating potential ISR-induced epigenetic changes, I found that chronic ISR activation increases repressive histone marks associated with closed chromatin and reduces activating marks linked to open chromatin. This indicates a shift toward a closed, heterochromatic state, which has been ultrastructurally observed in stressed microglia. In parallel, I found significant alterations in key metabolites involved in the regulation of these epigenetic modifications. Based on these findings, I hypothesize that chronic ISR activation in microglia promotes heterochromatic histone methylation in a metabolite-dependent manner. This proposal will address my hypothesis through two specific aims: Aim 1 will determine the impact of ISR on the in vitro metabolite production and consumption rates and in vivo microglial metabolomics. Aim 2 will determine the impact of ISR on metabolite-driven epigenetic changes in microglia by global and genome-wide mapping of histone modifications in vivo. Overall, this proposal will elucidate the potential role of the metabolic-epigenetic axis in ISR-dependent microglial reprogramming, providing insights into the mechanisms underlying neurodegeneration and informing potential therapeutic strategies. Combined with a comprehensive training plan that includes technical and scientific learning, as well as career development opportunities, this research training will equip me with the skills and expertise necessary to pursue a successful career as an independent scientist in academia. Project Number: 1F31AG099702-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Leen Aljayousi | Institution: ADVANCED SCIENCE RESEARCH CENTER, NEW YORK, NY | Award Amount: $34,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-Z (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11318565