Every organism, from a human to a fruit fly, relies on an internal
clock to regulate its daily activities and metabolic functions. Sleeping,
eating, and mating are optimized at different times depending on the organism
and the role it has in its ecological niche. Circadian rhythms are essential to
the well-being of any organism and their disruption can result in a variety of
different health concerns. A disrupted circadian clock can alter
the hormonal, autonomic, and metabolic functioning of organs. It has been discovered that
there is a link between sleep disruption and neurodegeneration. A common
neurodegenerative disorder seen amongst human populations is Alzheimer’s
Disease, affecting between 20 and 40 million people worldwide. Alzheimer’s has
been found to cause circadian dysfunction. Research into circadian biology, as
it is linked to neurodegeneration, can lead to a potential treatment of a very
prevalent disease.
Circadian rhythms are regulated by 24-hour feedback loop
oscillations of “clock genes”. These
genes are responsible for a variety of functions such as regulating membrane
electrical activity and cellular metabolism. The environment also plays a role
in regulating circadian rhythms. Light exposure activates a photoreceptor known
as melanopsin, which provides input to the suprachiasmatic nucleus (SCN) of the
hypothalamus. Neuronal and humoral signals are subsequently transmitted to
allow for communication with peripheral clocks in other regions of the brain and
visceral organs. This coordination between the central and peripheral clocks is
thought to be responsible for regulating metabolism.
When humans age, they typically experience a disruption of
the sleep-wake cycle in which they take more naps during the day and do not
experience a deep sleep at night. This, along with other altered circadian
oscillations that are associated with aging, might indicate that aging leads to
a decrease in circadian signaling. This could have detrimental effects on the
brain. Though Alzheimer’s disease is most often associated with memory loss,
another primary symptom of the disease is sleep disruption.
Both vertebrate and invertebrate models of neurodegenerative
disease have been studied and were found to have a disconnect between their
central and peripheral clocks, resulting in a disruption of circadian rhythms. In
addition, studies show that fluctuations in Ab levels in
cerebrospinal and interstitial fluid are associated with sleep-wake behavior. In
humans, these fluctuations decrease with age and with progression of
Alzheimer’s disease. Reduced production and clearance of Ab
through perivascular and glymphatic drainage channels as well as the increase
in interstitial fluid volume that occurs during sleep makes it essential to the
prevention and clearance of protein aggregates, thus reducing the risk of
neurodegenerative disease.
Metabolic disruption as caused by the desynchronization of
the circadian clock is a risk factor for type II diabetes, which is a known
risk factor for accelerated cognitive decline and Alzheimer’s. Temperature,
food availability, exercise, and social interactions are all manipulable factors
that are being considered as targets to re-regulate peripheral circadian
clocks.
Circadian rhythms have been found to have implications in a
variety of prevalent diseases such as type II diabetes and Alzheimer’s disease.
If researchers and physicians work to therapeutically resolve disruptions in
circadian rhythms, there is potential for resolution of metabolic functioning,
reducing the risk of type II diabetes. In addition, resolving circadian
disruptions could potentially prevent the cause and effect pattern of
neurodegenerative disorders.
Reference:
Chauhan, R., Chen, K.F., Kent, B.A., & Crowther, D.C.
(2017). Central and Peripheral Circadian
Clocks and Their Role in Alzheimer’s
Disease. Disease Models & Mechnisms, 10(10),
1187-
1199. doi: 10.1242/dmm.030627.
Hello Taylor,
ReplyDeleteThis is a fantastic blog on the link between circadian rhythms and neurodegeneration. I was particularly struck by the link between Type II diabetes and the acceleration of cognitive decline. I read a few articles and I found that circadian de-synchrony, which is linked to neurodegeneration, promotes obesity and inhibits glucose tolerance. The circadian clock is primarily maintained by the suprachiasmatic nucleus (SCN), as you discussed, which is found in the anterior hypothalamus. The SCN is linked to the sleep/wake cycle, food ingestion, and physical activity. The "clock genes" you mentioned have been identified in most tissues and cell types and they help to regulate metabolic processes including glucose and lipid homeostasis. Circadian de-synchrony impairs glucose control and prolonged exposure to circadian de-synchrony results in poor glucose tolerance. This seems to present a "chicken and the egg" type of dilemma when it comes to whether circadian rhythm disruption is the cause or the effect of neurodegeneration. This is especially true, given that type II diabetes is a known risk factor for accelerated neurological decline and neurological decline is know to disrupt circadian rhythm. Regardless of whether one causes the other, it is obvious that they are intrinsically linked to one another and controlling both circadian dysfunction and glucose homeostasis is important to impede neurodegeneration.
References:
Hutchison, A., Wittert, G., and Heilbronn, L. (2017). Matching meals to body clocks-impact on weight and glucose metabolism. Nutrients, 9(3), 222. http://doi.org/10.3390/nu9030222