Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Abstract

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 (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete proinflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation 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, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to agerelated and genetic forms of neurodegeneration.

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

“…Studies from multiple groups have recently improved our understanding of microglial function in disease and how it is impacted by genetic risk factors. Notably, lipid metabolism, storage, and processing has emerged as a potentially important contributor to proper microglial function in the CNS (Chan et al , ; Wang et al , ; Keren‐Shaul et al , ; Griciuc et al , ; Marschallinger et al , ; Nugent et al , ). This may indicate that TREM2‐stimulating therapeutic approaches could be employed in a variety of different clinical syndromes including AD, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, retinal degeneration, multiple sclerosis, and obesity‐associated metabolic syndromes.…”

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

“…By way of example, three DEGs in the SL metabolic pathway remained elevated in MyTrMaSt null mice but were reduced by SRT (Table 3 ); likewise some genes associated with cholesterol metabolism, and the three genes associated with lipoprotein metabolism and lipid droplets, including Plin4 , whose expression actually increased in MyTrMaSt null mice but reverted to control levels in mice treated with SRT. Lipid droplets have been implicated in neurodegeneration [ 29 , 38 ], in Parkinson’s disease [ 39 ], and in the aging brain [ 40 ] implying that they may play a broad role in neurodegenerative diseases. Similarly, lysosomal genes were unaffected in MyTrMaSt null mice but most reverted to control levels after SRT.…”

Cellular Specificity and Inter-cellular Coordination in the Brain Bioenergetic System: Implications for Aging and Neurodegeneration

“…Notably, apolipoprotein E-ε4 (APOE4), the strongest genetic risk factor for AD (Corder et al, 1993), reduces neuron-to-astrocyte transfer of fatty acids, which could be the underlying mechanism of the lipid dyshomeostasis seen in the disease (Liu et al, 2017). Additionally, LDs were also found to buildup in microglia of aged mouse or human brains, which then trigger ROS production and secretion of pro-inflammatory cytokines, and contribute to neurodegeneration (Marschallinger et al, 2019).…”