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

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. To determine the role of the central circadian clock in the suprachiasmatic nucleus (SCN) in regulating amyloid pathology, we crossed the 5xFAD amyloid mouse model with mice harboring deletion of the critical clock gene Bmal1 in GABAergic neurons using VGAT-iCre, which is expressed in >95% of SCN cells. To examine the role 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; Bmal1 fl/fl (VGAT-BMAL1KO;5xFAD) mice under varying light conditions. Amyloid plaque deposition, peri-plaque tau phosphorylation, and other pathology was examined by immunohistochemistry, and transcriptomic changes were examined by high-throughput qPCR. 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 (Psen1) -- which catalyzes the processing of sAPPβ into Aβ -- as well as APP cleavage to C-terminal fragments, were suppressed in VGAT-BMAL1KO;5xFAD under LD conditions. These studies elucidated an interaction between the circadian clock in GABAergic neurons and the light-dark cycle in regulating amyloid pathology and suggest that decoupling the central clock form the 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.