Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning

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.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

“…Our study demonstrates that C1q was involved in the microglial elimination of synapses in the CA1 region after repeated sevoflurane anesthesia. We also found that C1q was primarily produced by microglia rather than astrocytes, which is in line with recent studies [ 52 – 54 ]. Hence, we suppressed C1q expression using the specific antibody ANX005, which decreased synapse loss and improved memory and learning ability.…”

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer’s mouse model

“…The mean baseline fEPSP value was calculated and LTP was measured as the percentage change from baseline after TBS. Paired-pulse ratio (PPR) experiments were conducted, as previously described [7, 33] PPR responses to two impulses given at an interval of 10, 20, 50, 100, 200, or 500 ms were recorded. During baseline recording, 3 single stimuli (0.1 ms pulse width; 10 s intervals) were measured every 5 min and averaged for the 60 min fEPSP values.…”

Circadian Biology and the Neurovascular Unit

“…81 Microglia- Bmal1 deficiency leads to accelerated brain aging phenotypes including impaired synaptic pruning, learning and memory deficits, and disrupted sleep. 97 Interestingly, the effects of microglial Bmal1 deletion may actually be mediated by its downstream transcriptional target, Rev-erbα (reverse-ErbA-related receptor alpha). Diurnal oscillations in microglial synaptic phagocytosis occur in-phase with Bmal1 and antiphase of Rev-erbα , with Rev-erbα deletion abrogating these rhythms and locking the cell into a tonic state of increased phagocytosis, leading to loss of hippocampal synapses.…”