Circadian clocks, cognition, and Alzheimer's disease: synaptic mechanisms, signaling effectors, and chronotherapeutics

Abstract

Modulation of basic biochemical and physiological processes by the circadian timing system is now recognized as a fundamental feature of all mammalian organ systems. Within the central nervous system, these clock-modulating effects are reflected in some of the most complex behavioral states including learning, memory, and mood. How the clock shapes these behavioral processes is only now beginning to be realized. In this review we describe recent findings regarding the complex set of cellular signaling events, including kinase pathways, gene networks, and synaptic circuits that are under the influence of the clock timing system and how this, in turn, shapes cognitive capacity over the circadian cycle. Further, we discuss the functional roles of the master circadian clock located in the suprachiasmatic nucleus, and peripheral oscillator populations within cortical and limbic circuits, in the gating of synaptic plasticity and memory over the circadian cycle. These findings are then used as the basis to discuss the connection between clock dysregulation and cognitive impairments resulting from Alzheimer's disease (AD). In addition, we discuss the conceptually novel idea that in AD, there is a selective disruption of circadian timing within cortical and limbic circuits, and that it is the disruption/desynchronization of these regions from the phase-entraining effects of the SCN that underlies aspects of the early- and mid-stage cognitive deficits in AD. Further, we discuss the prospect that the disruption of circadian timing in AD could produce a self-reinforcing feedback loop, where disruption of timing accelerates AD pathogenesis (e.g., amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system. Lastly, we address potential therapeutic approaches that could be used to strengthen cellular timing networks and, in turn, how these approaches could be used to improve cognitive capacity in Alzheimer's patients.

Keywords: Alzheimer’s disease; Chronotherapeutics; Circadian; Cortex; Limbic system; Memory; Suprachiasmatic nucleus.

Fig. 1

Transcription feedback loops that form the basis of the circadian timing system. The red box denotes the feedback loop centered on the rhythmic expression of period and cryptochrome. The blue box denotes the feedback loop centered on the rhythmic expression of Bmal1 and Rev-Erbα/β. The orange box denotes rhythmic drive that is conferred to core clock-regulated genes (CCGs) via the Bmal1/Clock complex, and via the competitive interaction between Rev-Erbα/β and RORα/β/γ

Fig. 2

The SCN master clock: major efferents within the CNS, and clock-gated peripheral organ systems. Black arrows denote direct synaptic targets of the SCN. Red arrows denote cortico-limbic brain regions that are under the indirect control of the SCN, either via output from the lateral septal area (LS), or via glucocorticoid (GC) release from the adrenal gland. Blue arrows denote SCN output via the hypothalamic pituitary axis (HPA) and the autonomic nervous system (ANS) that gates the inherent oscillatory capacity of peripheral organs. The brown arrow denotes the direct, monosynaptic, input to the SCN from the retina. sPVZ: subparaventricular zone; PVNT: paraventricular nucleus of the thalamus; BNST: bed nuclei of the stria terminalis; OVLT: organ vascular of lamina terminalis; POA: preoptic area; PVN: paraventricular nucleus; DMN: dorso-medial nucleus; Hipp: hippocampus; CTX: cortex

Fig. 3

Depiction of the hypothesized process by which AD leads to a cellular and systems-level disruption of circadian timing within cortico-limbic circuits. A further description of the model is presented in the Conclusion section