MECHANISMS UNDERLYING MICROGLIA DYSFUNCTION DURING NEURODEGENERATION

National Institute Of Environmental Health Sciences

Investigators

Abstract

Microglia, the resident immune cells of the brain, were first described as sensors of pathological events. However, evidence showing that systemic inflammation can exacerbate symptoms of neurodegeneration, including cognitive decline during Alzheimer's disease (AD), has revealed an active role for microglia in the disease progression. Moreover, identification of disease associated genetic risk variants that disrupt microglia function further reinforced the notion that microglia are not just responding, but actively contributing to neurodegeneration. Transcriptional and chromatin profiles of brain cells and tissues from mouse models of AD-like neurodegeneration and post-mortem brains of AD patients provided key evidence for the essential role of microglia in AD progression. Specifically, our previous high-throughput studies identified noncoding DNA regions that regulate gene expression changes underlying AD. Notably, we found that regions regulating immune response pathways were specifically enriched for AD-associated genetic risk variants, suggesting that genetic predisposition to AD is encoded in the brain immune function. These studies also identified key proteins, such as transcriptional regulators and chromatin modifiers, that target AD-relevant regulatory regions and mediate gene expression changes during AD. In particular, we recently demonstrated that the immune transcriptional factor PU.1 and its downstream target Lag3 play an important role in Alzheimer's disease progression and inhibiting the activity of these immune regulators can alleviate multiple neurodegeneration phenotypes. Ongoing research using human-derived microglia as well as organoids, is aimed at dissecting the mechanisms by which genetic and environmental risk factors alter the regulation of microglia immune function and lead to increasing susceptibility to AD.