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

Nat Neurosci, 2020 · DOI: 10.1038/s41593-019-0566-1 · Published: February 1, 2020

Simple Explanation

As the brain ages, microglia, the brain's immune cells, become more activated and dysfunctional. These cells start accumulating lipid droplets, which are storage units for fats. This study found that these lipid droplet-accumulating microglia (LDAM) are less effective at clearing debris and produce harmful substances. Researchers identified several genes that control the formation of these lipid droplets. Interestingly, some of these genes are linked to human neurodegenerative diseases, suggesting a connection between LDAM and age-related brain disorders. The study suggests that LDAM represent a harmful state of microglia in the aging brain, contributing to inflammation and potentially playing a role in the development of neurodegenerative diseases.

Study Duration

Not specified

Participants

Aged C57BL/6J male wild type mice (18–20 months old), young C57BL/6J males (2–4 months of age), Grn−/− deficient mice and wild type littermates, Human hippocampal tissue sections from autopsy samples of young adult (<35 years, n=3) and elderly (>60 years, n=5) humans

Evidence Level

Level 2: Experimental study using animal models and human tissue samples

Key Findings

1
Microglia in aged mouse and human brains accumulate lipid droplets, forming lipid droplet-accumulating microglia (LDAM).
2
LDAM exhibit a unique transcriptional profile distinct from other known microglial states, characterized by dysregulation of phagocytosis and increased production of reactive oxygen species (ROS) and pro-inflammatory cytokines.
3
A CRISPR-Cas9 screen identified genes linked to neurodegeneration (SLC33A1, SNX17, GRN, VPS35) as genetic regulators of lipid droplet formation in microglia, and GRN−/− mice showed increased LDAM accumulation with functional impairments.

Research Summary

The study identifies a novel state of microglia in the aging brain, characterized by the accumulation of lipid droplets (LDAM). LDAM exhibit a unique transcriptional signature, functional deficits in phagocytosis, and increased production of ROS and pro-inflammatory cytokines. Genetic screening implicates genes linked to neurodegeneration as regulators of lipid droplet formation, suggesting a role for LDAM in age-related neurodegenerative diseases.

Practical Implications

Therapeutic Target Identification

Targeting LDAM could represent a novel therapeutic approach to decrease neuroinflammation and restore brain homeostasis in aging and neurodegeneration.

Understanding Neurodegenerative Disease Mechanisms

The identification of genes that regulate lipid droplet formation in microglia and are also linked to neurodegenerative diseases provides insights into the pathogenesis of these disorders.

Biomarker Development

LDAM could serve as a biomarker for identifying individuals at risk of developing age-related neurodegenerative diseases.

Study Limitations

1
The study primarily focuses on the hippocampus, and further research is needed to determine the prevalence and function of LDAM in other brain regions.
2
The exact mechanisms by which lipid droplet accumulation leads to microglial dysfunction remain to be fully elucidated.
3
Further investigation is required to determine the specific contribution of LDAM to the pathogenesis of different neurodegenerative diseases.

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