Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic
Chinyere Agbaegbu Iweka1, Erica Seigneur2, Amira Latif Hernandez1
1Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA.
Abstract:
Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11bcre;Bmallox/lox mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11bcre;Bmallox/lox mice also showed deficits in the sleep-wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain.
Insights
Aging brains show impaired cognitive function and sleep due to loss of microglial circadian rhythms. Loss of BMAL1 in microglia accelerates aging deficits, impacting synaptic pruning and brain homeostasis.
Area of Science:
- Neuroscience
- Immunology
- Chronobiology
Background:
- Aging impairs circadian immune responses in peripheral macrophages.
- Microglia, the brain's immune cells, exhibit diurnal rhythms influencing immune responses and synaptic remodeling.
- The role of microglial circadian rhythmicity in aging remains underexplored.
Purpose of the Study:
- To investigate the interplay between aging and microglial circadian rhythmicity.
- To examine the function of the core clock transcription factor BMAL1 in microglia during aging.
Main Methods:
- Utilized aging mice deficient in the BMAL1 gene (Cd11bcre;Bmallox/lox).
- Assessed cognitive function, hippocampal long-term potentiation, and dendritic spine morphology.
- Analyzed C1q deposition and synaptic engulfment by microglia.
Main Results:
- Aging Bmal1-deficient mice exhibited accelerated cognitive decline and impaired hippocampal long-term potentiation.
- Increased immature dendritic spines were observed in aging Bmal1-deficient mice.
- BMAL1 deficiency in microglia reduced C1q deposition and synaptic pruning, alongside disrupted sleep-wake cycles.
Conclusions:
- Microglial BMAL1 is crucial for maintaining synaptic homeostasis in the aging brain.
- Loss of microglial circadian rhythmicity contributes to age-associated cognitive and sleep deficits.
- BMAL1 plays a significant role in regulating synaptic pruning in aging microglia.
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