Association between circadian rhythms and neurodegenerative diseases

Abstract

Dysfunction in 24-h circadian rhythms is a common occurrence in ageing adults; however, circadian rhythm disruptions are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias, and Parkinson's disease. Manifestations of circadian rhythm disruptions differ according to the type and severity of neurodegenerative disease and, for some patients, occur before the onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that circadian rhythm disruptions, in addition to being a symptom of neurodegeneration, might also be a potential risk factor for developing Alzheimer's disease and related dementias, and Parkinson's disease, although large, longitudinal studies are needed to confirm this relationship. The mechanistic link between circadian rhythms and neurodegeneration is still not fully understood, although proposed underlying pathways include alterations of protein homoeostasis and immune and inflammatory function. While preliminary clinical studies are promising, more studies of circadian rhythm disruptions and its mechanisms are required. Furthermore, clinical trials are needed to determine whether circadian interventions could prevent or delay the onset of neurodegenerative diseases.

Figure 1.. Proposed bi-directional relationship between CRD and neurodegeneration.

The core circadian clock is present in most cells, including those of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), and consists of a transcriptional-translational feedback loop involving the positive transcriptional regulators CLOCK and BMAL1, and their negative feedback inhibitors PERIOD, CRYTOCHROME, and REV-ERB proteins. The circadian clock influences sleep timing, which has been shown to directly control Aβ dynamics (in humans (90) and mice (87,88)) and glymphatic clearance of toxic proteins (in animals (76)). Sleep disruption also alters a host of other factors, from synaptic homeostasis to inflammation. Circadian clocks in microglia and astrocytes (glial clocks) may regulate the blood-brain barrier (BBB), inflammation, and synaptic function (78, 83, 92, 93)(109), though the evidence is too preliminary to draw a strong conclusion. Animal studies suggest that circadian clocks in neurons influence brain oxidative stress (78), and could affect brain metabolic function and synaptic homeostasis (78). Finally, peripheral clocks in organs such as the gut, liver, and immune tissue impact peripheral metabolism, the microbiome, and immune function (79). It is proposed that this multi-system perturbation could promote toxic protein aggregation and neurodegeneration, which in turn could disrupt circadian clocks in the SCN and periphery. Black arrows=supported by human data, Blue arrows=supported by animal data, Grey arrows=data is suggestive but too preliminary to draw firm conclusions.