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

Chinyere Agbaegbu Iweka; Erica Seigneur; Amira Latif Hernandez; Sur Herrera Paredes; Mica Cabrera; Eran Blacher; Connie Tsai Pasternak; Frank M Longo; Luis de Lecea; Katrin I Andreasson

doi:10.1186/s12974-023-02727-8

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

J Neuroinflammation. 2023 Feb 24;20(1):48. doi: 10.1186/s12974-023-02727-8.

Authors

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA.
² Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
³ Department of Biology, Stanford University, Stanford, CA, USA.
⁴ Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, 9190401, Jerusalem, Israel.
⁵ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁶ Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA. kandreas@stanford.edu.
⁷ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. kandreas@stanford.edu.
⁸ Stanford Immunology Program, Stanford University, Stanford, CA, USA. kandreas@stanford.edu.
⁹ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA. kandreas@stanford.edu.

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 Cd11b^cre;Bmal^lox/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, Cd11b^cre;Bmal^lox/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.

Keywords: BMAL1; Circadian clock; Microglia; Sleep–wake cycle; Synaptic plasticity.

MeSH terms

ARNTL Transcription Factors / genetics
ARNTL Transcription Factors / metabolism
Animals
CLOCK Proteins / genetics
Cognitive Aging*
Mice
Microglia* / metabolism
Neuronal Plasticity

Substances

CLOCK Proteins
ARNTL Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding