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

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 gene 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 ( 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.