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

introductionCircadian rhythm disruption is an early symptom of Alzheimer's disease (AD), though it remains unclear how the light-dark (LD) cycle and the central circadian clock in the suprachiasmatic nucleus (SCN) influence AD pathobiology.

methodsWe disrupted the SCN clock via deletion of Bmal1 in GABAergic neurons (VGAT-iCre; Bmal1 KO), crossed to the 5xFAD amyloid-beta (Aβ) model, and raised mice under LD or constant dark (DD) conditions. We examined circadian rhythms, sleep, Aβ plaques, and phospho-tau (p-tau) pathology, and gene expression.

resultsVGAT-Bmal1 knockout (KO) mice showed weakened rhythms in LD and arrhythmicity in DD conditions. LD conditions promoted Aβ plaque accumulation in 5xFAD mice, while VGAT-Bmal1 deletion reduced amyloid precursor protein (APP) cleavage, Aβ plaque accumulation, and peri-plaque p-tau, and induced extracellular matrix (ECM) gene expression in LD, but not DD, conditions. DISCUSSION: In 5xFAD mice, LD cycles interact with the central circadian clock to reinforce Aβ deposition, while central clock disruption or constant darkness unexpectedly mitigate plaque pathology. HIGHLIGHTS: 5xFAD mice accumulate more Aβ plaque pathology when raised under standard LD conditions than when raised in DD conditions. VGAT-Bmal1 KO eliminates locomotor rhythms in DD conditions and weakens locomotor, sleep, and transcriptional rhythms in LD conditions. VGAT-Bmal1 KO; 5xFAD mice aged in LD conditions accumulated less total Aβ plaque and peri-plaque p-tau than their Cre- littermates. VGAT-Bmal1 KO had no effect onplaque pathology in mice aged in constant darkness. Amyloid precursor protein carboxy terminal fragments (APP-CTFs) were suppressed in VGAT-Bmal1 KO mice under LD conditions, suggesting reduced Aβ production. Transcriptomic analysis shows induction of AEBP1 in VGAT-Bmal1 KO, which regulates ECM genes and has been associated with AD pathology in humans.