Circadian rhythms and the light-dark cycle interact to regulate amyloid plaque accumulation and tau phosphorylation in 5xFAD mice

Apr 16, 2025bioRxiv : the preprint server for biology

Body clock and day-night cycle together influence amyloid buildup and tau changes in Alzheimer’s model mice

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Abstract

VGAT-BMAL1KO;5xFAD mice showed reduced total plaque accumulation and peri-plaque tau phosphorylation under light-dark conditions compared to controls.

Disruption of the central circadian clock was observed in VGAT-BMAL1KO;5xFAD mice, leading to severe behavioral rhythm disturbances in both light-dark and constant darkness environments.
Under regular light-dark cycles, specific reductions in amyloid plaque accumulation and tau phosphorylation were noted in VGAT-BMAL1KO;5xFAD mice.
No reduction in amyloid pathology was observed in VGAT-BMAL1KO;5xFAD mice maintained in constant darkness.
Control 5xFAD mice also exhibited decreased plaque accumulation in constant darkness compared to light-dark conditions.
Lower expression of presenilin 1 and suppression of amyloid precursor protein cleavage occurred in VGAT-BMAL1KO;5xFAD mice specifically under light-dark conditions.

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BACKGROUND: Circadian disruption has long been appreciated as a downstream consequence of Alzheimer's Disease in humans. However, an upstream role for behavioral circadian disruption in regulating AD pathology remains an open question.

METHODS: To determine the role of the central circadian clock in the suprachiasmatic nucleus (SCN) in regulating amyloid pathology, we generated mice harboring deletion of the critical clock genein GABAergic neurons using VGAT-iCre, which is expressed in >95% of SCN cells, and crossed this line to the 5xFAD amyloid mouse model. To examine the role of the light-dark cycle in this process, we aged these mice in either regular 12:12 light-dark (LD) or constant darkness (DD) conditions. Transcriptional, behavioral, and physiological rhythms were examined in VGAT-iCre;; 5xFAD (VGAT-BMAL1KO;5xFAD) mice under varying light conditions. Amyloid plaque deposition, peri-plaque tau phosphorylation, glial activation, and transcriptomic changes were examined. Bmal1Bmal1fl/fl

RESULTS: VGAT-BMAL1KO;5xFAD mice showed loss of SCN BMAL1 expression and severe disruption of behavioral rhythms in both LD and DD, with loss of day-night rhythms in consolidated sleep and blunting of rhythmic clock gene expression in the brain. Surprisingly, VGAT-BMAL1KO;5xFAD mice kept under LD showed reduced total plaque accumulation and peri-plaque tau phosphorylation, compared to Cre-negative controls. These changes were gated by the light-dark cycle, as they were absent in VGAT-BMAL1KO;5xFAD mice kept in DD conditions. Total plaque accumulation was also reduced in control 5xFAD mice kept in DD as compared to LD, suggesting a general effect of light-dark cycle on amyloid aggregation. Expression of murine presenilin 1 (), as well as amyloidogenic cleavage of amyloid precursor protein, were suppressed in VGAT-BMAL1KO;5xFAD specifically under LD conditions. Psen1

CONCLUSIONS: In 5xFAD mice, the central circadian clock and the light-dark cycle interact to regulate amyloid pathology. Disruption of the central clock in the presence of a light-dark cycle may reduce APP cleavage and plaque formation. These results call into question the proposed simple positive feedback loop between circadian rhythm disruption and Alzheimer's Disease pathology.

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Circadian rhythms and the light-dark cycle interact to regulate amyloid plaque accumulation and tau phosphorylation in 5xFAD mice

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