Central and peripheral circadian clocks and their role in Alzheimer's disease

Abstract

Molecular and cellular oscillations constitute an internal clock that tracks the time of day and permits organisms to optimize their behaviour and metabolism to suit the daily demands they face. The workings of this internal clock become impaired with age. In this review, we discuss whether such age-related impairments in the circadian clock interact with age-related neurodegenerative disorders, such as Alzheimer's disease. Findings from mouse and fly models of Alzheimer's disease have accelerated our understanding of the interaction between neurodegeneration and circadian biology. These models show that neurodegeneration likely impairs circadian rhythms either by damaging the central clock or by blocking its communication with other brain areas and with peripheral tissues. The consequent sleep and metabolic deficits could enhance the susceptibility of the brain to further degenerative processes. Thus, circadian dysfunction might be both a cause and an effect of neurodegeneration. We also discuss the primary role of light in the entrainment of the central clock and describe important, alternative time signals, such as food, that play a role in entraining central and peripheral circadian clocks. Finally, we propose how these recent insights could inform efforts to develop novel therapeutic approaches to re-entrain arrhythmic individuals with neurodegenerative disease.

Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection

“…Given that SIRT1 is highly specialized distributed in the hypothalamic nuclei, it is no surprise that brain SIRT1 is a major contributor to the systemic network of metabolic homeostasis. It should be noted that, nowadays, accumulated evidence supports a reciprocal relationship between brain and peripheral tissues in metabolic benefits, circadian oscillations and neurological functions ( 133 , 134 ). Although we only discussed SIRT1 in the brain, SIRT1 in various peripheral organs also mediates metabolism and circadian rhythms through sensing environmental cues and feeding back into the homeostatic network ( 13 , 133 ).…”

Interacting influences of aging and Alzheimer's disease on circadian rhythms

“…There is a growing interest in the role of peripheral oscillators in regulating circadian rhythms and health. How alterations in these peripheral oscillators may contribute to AD is an important question that has been considered in recent reviews (Chauhan et al., ; Kent, ).…”

“…This review focuses on brain clocks, especially the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. Peripheral clocks and their interactions with feeding and metabolism will be mentioned briefly, but readers are referred to other articles for a more extensive discussion of the role of these factors in AD (Chauhan, Chen, Kent, & Crowther, ; Kent, ). Finally, the current review will discuss potential strategies for ameliorating age‐ or AD‐related circadian rhythm disruption.…”

Aging and the clock: Perspective from flies to humans

“…Thus, it appears that the aging induces impairments in circadian neural output activity and circuit connectivity resulting in decreased circuit synchronization. Desynchronization between the central oscillator and peripheral oscillators can exacerbate disease pathology and accelerate mortality (Chauhan, Chen, Kent & Crowther, ; Zuurbier et al., ).…”