Myeloid deficiency of the intrinsic clock protein Bmal1 accelerates cognitive aging by disrupting microglial synaptic pruning

Iweka, C. A.; Seigneur, E. M.; Hernandez, A. L.; Herrera Paredes, S.; Cabrera, M.; Blacher, E.; Pasternak, C.; Longo, F.; de Lecea, L.; Andreasson, K.

doi:10.1101/2022.10.17.512618

bioRxiv · 10.1101/2022.10.17.512618

Myeloid deficiency of the intrinsic clock protein Bmal1 accelerates cognitive aging by disrupting microglial synaptic pruning

Iweka, C. A.·Seigneur, E. M.·Hernandez, A. L.·Herrera Paredes, S.·Cabrera, M.·Blacher, E.·Pasternak, C.·Longo, F.·de Lecea, L.·Andreasson, K.

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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. Significance StatementThis study demonstrates that myeloid deficiency of the circadian clock gene Bmal1 disrupts microglial synaptic pruning in the hippocampus, accelerates age-associated cognitive decline, and disrupts the sleep-wake cycle.

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Iweka, C. A., Seigneur, E. M., Hernandez, A. L., Herrera Paredes, S., Cabrera, M., Blacher, E., Pasternak, C., Longo, F., de Lecea, L., Andreasson, K.. 2022-10-18. Myeloid deficiency of the intrinsic clock protein Bmal1 accelerates cognitive aging by disrupting microglial synaptic pruning. https://doi.org/10.1101/2022.10.17.512618

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