The regulation of the microglial response to amyloid-beta plaques by the polycomb repressive complex 2

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Project Summary/Abstract A gap exists in our understanding of the pathophysiology behind Alzheimer’s Disease (AD), which has led to virtually nonexistent treatment options. Recent studies have identified microglia, the innate immune cells of the brain, as key players in the response to AD that may help us fill this gap. Specifically, microglia appear to play a protective role against toxicity associated with amyloid-ß containing plaques. Through activation of the triggering receptor expressed in myeloid cells 2 (TREM2) signaling pathway, microglia migrate towards and surround these plaques while inducing a distinct transcriptional signature known as the Disease Associated Microglia (DAM) phenotype. An important outstanding question is how microglia regulate this state, both transcriptionally and functionally. Our lab has previously identified the polycomb repressive complex 2 (PRC2) as an important epigenetic regulator of brain region specific microglia subpopulations. PRC2 is an epigenetic complex involved in gene silencing and has also been implicated as a signaling regulator in immune cells. Notably, we found that PRC2 deficient microglia downregulate many genes in the TREM2 signaling pathway. I hypothesize that PRC2 controls the microglial response to amyloid-ß containing plaques in a TREM2- dependent mechanism. In support of this, I generated a PRC2-deficient microglia mouse line crossed to the 5xFAD amyloid model of AD and showed that PRC2-deficiency leads to loss of plaque associated microglia, similar to TREM2-deficient models. This could be due to transcriptional regulation of the TREM2 pathway or direct modulation of TREM2 signaling. To further investigate my hypothesis, I will first characterize the epigenetic and transcriptional role PRC2 plays in 5xFAD microglia. There are multiple TREM2-dependent mechanisms that could lead to decreased plaque associated microglia – inability to sense plaques, increased death at the plaques, or lack of migration towards the plaques. To determine if PRC2 regulates these phenotypes in a TREM2-dependent manner, I will culture primary mouse microglia and pharmacologically inhibit PRC2, followed by induction of TREM2 signaling. With this model, I will assay TREM2-dependent sensing, survival, and migration. The results of this proposal will reveal whether PRC2 is a master regulator of the microglial response to AD amyloid-ß containing plaques through its control of TREM2 signaling, either transcriptionally or through direct regulation of the signaling pathway. These data are critical to furthering our understanding of how microglial functional states are regulated, opening avenues for the development of effective treatments against Alzheimer’s Disease.