In 5xFAD mice, light-dark conditions and central circadian clock disruption shaped amyloid plaque and peri-plaque p-tau pathology.
Evidence
This mouse genetic and environmental experiment crossed VGAT-Bmal1 knockout with 5xFAD mice and compared light-dark versus constant-dark rearing for rhythms, sleep, plaques, phospho-tau, and gene expression.
Caveat
The effect was specific to a mouse Alzheimer's model and housing condition, since VGAT-Bmal1 knockout reduced plaque pathology in light-dark conditions but not constant darkness.
Simplified
INTRODUCTION: 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.
METHODS: We disrupted the SCN clock via deletion of Bmal1 in GABAergic neurons (VGAT-iCre; Bmal1 KO), crossed to the 5xFAD (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.
RESULTS: 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.
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.
Key numbers
40%
Reduction in Aβ Plaque Density
Density of Aβ plaques in the cortex of VGAT-Bmal1 KO;5xFAD mice
>75%
Reduction in Peri-Plaque p-Tau
Amount of phosphorylated tau around Aβ plaques in VGAT-Bmal1 KO;5xFAD mice
70%
Aβ Plaque Accumulation in LD vs. DD
Increase in fibrillar plaques in 5xFAD mice raised in light-dark conditions compared to constant darkness
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Circadian Biology