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Naturally-aged microglia exhibit phagocytic dysfunction accompanied by gene expression changes reflective of
Alyssa L Thomas1,2,3, Maria A Lehn3,4, Edith M Janssen3,5
1Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Abstract:
Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer's disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ. Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.
Insights
Naturally aged microglia show reduced ability to clear amyloid-beta plaques, a key factor in Alzheimer's disease progression. This dysfunction is linked to broad gene expression changes and diminished TREM2 receptor levels.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglial dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
- Age-related decline in myeloid cell phagocytosis is known, but studies on normally aged microglia are limited.
- Existing data often derive from accelerated genetic AD models, not natural aging.
Purpose of the Study:
- To investigate phagocytosis of amyloid-beta (Aβ) by naturally aged microglia.
- To identify gene expression differences between young and aged microglia with varying phagocytic capacities.
- To elucidate mechanisms underlying age-related microglial dysfunction in AD.
Main Methods:
- Comparative analysis of gene expression in young versus naturally aged microglia.
- Assessment of Aβ phagocytosis in microglia from different age groups.
- Evaluation of TREM2 (triggering receptor expressed on myeloid cells 2) expression and its correlation with Aβ uptake.
Main Results:
- Naturally aged microglia exhibited reduced Aβ phagocytosis over time compared to young microglia.
- Aged microglia displayed broad gene expression changes indicative of widespread dysfunction, irrespective of phagocytic status.
- Downregulation of phagocytic receptors, including TREM2, was observed in aged microglia.
- Diminished TREM2 protein levels correlated with impaired Aβ uptake, suggesting a role in microglial phagocytic defects.
Conclusions:
- Normally aged microglia exhibit significant changes in gene expression, leading to impaired Aβ phagocytosis.
- Defects in microglial phagocytic capacity, potentially mediated by reduced TREM2, contribute to Alzheimer's disease progression.
- These findings highlight the impact of natural aging on microglial function and AD pathogenesis.
