Circadian rhythms and the light-dark cycle interact to regulate amyloid-beta plaque accumulation and tau...

Circadian 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.

We 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.

VGAT-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.

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.

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.