The Circadian Regulation of γ-Secretase Activity

Although the cause of Alzheimer’s disease (AD)is poorly understood, the disease progression is associated with β-amyloid (Aβ) plaques and Tau tangles in the brain.Aβ peptides are products of amyloid precursor protein cleavage by γ-secretase, an intramembrane protein complex comprised of four essential subunits, Presenillin, Nicastrin, Anterior pharynx-defective-1α and Presenilin-enhancer2.In addition, sleeping disorders are common in AD patients suggesting malfunction in the internal biological clock. The circadian rhythm,a roughly 24-hour cycle, governs daily physiological processes and is controlled by a complex network of molecular transcriptional-translational feedback loops. The core machinery of the circadian clock is composed of the transcription factor BMAL1, which binds with CLOCK and transcribes numerous genes including the negative clock-repressors genes Per, Cry and Reverb which in turn suppress the expression of Bmal1 and Clock.Aβ secretion in the ISF of an AD transgenic mice model exhibits a robust circadian-like 24-hour oscillation.However,the effect of circadian rhythm on γ-secretase activity has yet been investigated. Here we describe a novel circadian pattern of γ-secretase activity which is independent of the expression of the core essential subunits.This oscillation in activity is regulated by the molecular machinery of the circadian clock demonstrated by depleting the central clock protein BMAL1 both in vitro and in vivo. Interestingly, in an AD mouse model (5XFAD), circadian γ-secretase activity is not modified in early stage of disease progression suggesting that γ-secretase activity, regardless of PS FAD mutation, is controlled by circadian rhythm.This work provides the first evidence of a connection between γ-secretase activity and the circadian rhythm.