Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive memory loss. Microglia, the resident immune cells of the central nervous system (CNS), have been heavily studied in their relation to the disease, as they exhibit both neuroprotective and neurodegenerative effects. Our lab has shown the transcription factor PPAR-delta to be neuroprotective in Huntington’s disease, and microglia are among the highest expressers of PPAR-delta in the CNS. Additionally, PPAR-delta is currently the focus of a Phase II clinical trial for AD, thus understanding the effects of PPAR-delta in microglia is paramount. To address this, we began by taking an unbiased transcriptomic approach. Mice were treated with PPAR-delta agonist for six weeks and gene expression changes in microglia were assessed. We then moved to carry out experiments in an iPSC-derived model of microglia. We utilized experimental procedures including cytokine arrays, phagocytosis assays, migration assays, and single-cell transcriptomics to further characterize the microglial response to PPAR-delta agonism.
Preliminary transcriptomic results revealed that long term treatment with PPAR-delta agonism reduced inflammatory processes in microglia in vivo. Follow-up studies in the iPSC models of microglia further bolstered that PPAR agonism reduces secretion of pro-inflammatory mediators, reduces migration of microglia, and increases phagocytosis of disease relevant substrates (e.g., amyloid-beta and synaptosomes). Single-cell transcriptomics of the iPSC-derived microglia tie these findings together and demonstrate that PPAR-delta agonism shifts microglia to a state that is high in lipid-processing and phagocytic genes, but represses inflammatory mediator production.
We also set out to understand the mechanistic basis of PPAR-delta activity in microglia after preliminary data revealed that PPAR-delta is capable of phase separation. Though more experimentation in this area is necessary, preliminary results indicate that PPAR-delta undergoes phase separation with the transcriptional coactivator Mediator 1 (Med1) to carry out its function. Additionally, PPAR-delta interacts with PU.1, a master transcription factor for microglia that is a genetic risk factor for AD, and this interaction is decreased by PPAR-delta agonist treatment.
The culmination of these experiments suggests that PPAR-delta agonism may be beneficial in the AD brain because it appropriately activates microglia to respond to AD pathology (e.g., phagocytosis) while reducing subsequent inflammation, and that these functions are related to PPAR-delta interactions with Med1 and PU.1.
