Aging Immune Cells may Contribute to Neurodegenerative Disease

Studying and understanding the causes of neurodegenerative diseases poses a substantial challenge. By the time symptoms of disease begin to appear, the causative changes within the brain have already occurred. We are therefore left to speculate whether features of dementia patients’ brains are a cause, or merely a consequence of the disease.

Microglia are the brain’s resident immune cells, and have long been observed to alter their activity in neurodegenerative disease. However, through a combination of lack of research and the reasons outlined above, their role in disease is not well understood.

Research published in Nature Neuroscience shows that a subset of microglia in aging brains develop a dysfunctional, pro-inflammatory phenotype reminiscent of the foam cell macrophages that drive atherosclerosis. These microglia accumulated lipid droplets, released reactive oxygen species and inflammatory mediators, and had impaired phagocytosis.

However, the most surprising and interesting finding involved the genes that regulate lipid droplet formation. Researchers found that variants of several of these genes had already been linked to neurodegenerative disease. This would seem to indicate that microglia are drivers of disease, and that targeting microglia to reduce inflammation could one day help prevent or treat neurodegeneration.

Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call ‘lipid-droplet-accumulating microglia’ (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR–Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

Marschallinger, J., Iram, T., Zardeneta, M., Lee, S., Lehallier, B., & Haney, M. et al. (2020). Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature Neuroscience. doi: 10.1038/s41593-019-0566-1