TY - JOUR
T1 - Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning
AU - Iweka, Chinyere Agbaegbu
AU - Seigneur, Erica
AU - Hernandez, Amira Latif
AU - Paredes, Sur Herrera
AU - Cabrera, Mica
AU - Blacher, Eran
AU - Pasternak, Connie Tsai
AU - Longo, Frank M.
AU - de Lecea, Luis
AU - Andreasson, Katrin I.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - BMAL1
KW - Circadian clock
KW - Microglia
KW - Sleep–wake cycle
KW - Synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=85148949081&partnerID=8YFLogxK
U2 - 10.1186/s12974-023-02727-8
DO - 10.1186/s12974-023-02727-8
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C2 - 36829230
AN - SCOPUS:85148949081
SN - 1742-2094
VL - 20
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 48
ER -