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 Alzheimers disease (AD), has revealed an active role for microglia in the disease progression. Moreover, identification of disease associated genetic risk variants that perturb 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. These high throughput studies led to the identification of noncoding DNA regions that regulate gene expression changes underlying AD. Importantly, they demonstrated that regions which regulate immune response pathways were specifically enriched for AD-associated genetic risk variants, thus suggesting that genetic predisposition to AD is encoded in the brains 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. Ongoing research 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.