May 31, 2023

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Neurodegeneration and the Circadiian Clock

Neurodegeneration and the biological clock


Neurodegeneration and the Circadiian Clock.  Suzane Hood et al. published an article entitled “Neurodegeneration and the Circadiian Clock” on Front Aging Neuri in 2017. Circadian rhythm and neurodegenerative diseases

With the increase in life expectancy worldwide, the prevalence of neurodegenerative diseases has steadily increased. Worldwide, Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) are the most common neurodegenerative diseases and are associated with a significant burden on the health care system.

Although the pathogenesis is different and the symptoms are diverse, what AD, PD and HD have in common is the interruption of the circadian rhythm, or the cyclical fluctuations of nearly 24 hours in many physiological and behavioral processes. A rapidly developing study has shown that disturbances in the circadian rhythm system precede the appearance of the characteristic cognitive and motor symptoms of these diseases and may lead to their onset.

Here, we provide a concise overview of the evidence for the link between the circadian system and these diseases, and examine acyclic methods for the treatment of AD, PD, and HD. The circadian rhythm and the cellular clock circadian system provide an adaptive mechanism for organisms to coordinate cellular processes, physiological functions and behaviors with the predictable 24-hour cycle of light and darkness on the earth.

In humans, familiar examples of rhythms include daily sleep and wake patterns; rise and fall of core body temperature; heart rate; blood pressure; and the release of various hormones, such as the nighttime surge of melatonin in the pineal gland. When the predictable time cues are removed, the existence of the endogenous timing system in the body is clearly visible, but the nearly 24-hour rhythm in these processes still exists.

In mammals, the suprachiasmatic nucleus (SCN) houses the main biological clock and is located on the dorsal side of the optic chiasm. The SCN input from the retinoic hypothalamic tract provides information about daily light in order to synchronize the internal clock with the external environment.

In turn, SCN transmits time of day information to a series of peripheral oscillators in various regions and organs of the brain (such as the heart, lungs, liver, and adrenal glands) through synapses and diffusion signals.

Therefore, the central nervous system is used to coordinate the timing of the clock network distributed throughout the body. This coordination is essential for health and well-being: Circadian rhythm disorders have been associated with many disease states, including some cancers, metabolic diseases, and mood disorders such as bipolar disorder and major depression.

As shown in Figure 1, the circadian timing mechanism is controlled at the cellular level by a set of genes that regulate their own transcription and translation in about 24 hours through a series of interacting negative feedback loops.

In addition to regulating its own expression level, “clock” genes also act as transcription factors for other genes, which regulate a variety of functions, including cell division, metabolism, immune response, and oxidation processes. Importantly, mutations in the bmal1 and period genes produced accelerated aging phenotypes in Drosophila and mice. Compared with the age-matched wild-type control group, tissues declined faster, cognitive function was impaired, and life span was shorter.

Neurodegeneration and the Circadiian Clock



Circadian symptoms of Alzheimer’s disease, Parkinson’s disease and Huntington’s disease

Like other physiological processes, the activity of the circadian system undergoes significant changes during a lifetime, with interruptions in some rhythms, such as sleep/wake cycles and hormone release in adults. Importantly, some age-related rhythm disorders are similar to the circadian rhythm disorders observed in AD, PD, and HD, which will be reviewed in the following chapters.

While noting these similarities, it is important to recognize that the severity and timing of circadian rhythm disorders in Alzheimer’s disease, Parkinson’s disease, and hemodialysis patients are different from those during healthy aging. By more clearly distinguishing between the rhythmic changes that reflect the neurodegenerative process and the rhythmic changes that are not necessarily pathological, we may be able to more easily recognize the development of the disease and may improve the prospects for intervention and care.



Sleep/wake rhythm

The disorder of sleep/wake rhythm may be the most significant circadian rhythm-related symptom in individuals affected by AD, PD, or HD. As these diseases progress, nighttime sleep becomes more and more fragmented, while nighttime activity levels and daytime sleepiness increase.

In severe cases, there is very little difference in activity and sleep time during the day and night. These observed poor integration of human rest/activity patterns are parallel to animal models of each disease state.

In addition, behavioral sleep disorders such as restless legs syndrome and rapid eye movement behavior disorder (RBD) are highly comorbid with Parkinson’s disease.

In short, normal sleep/wakefulness rhythms and decreased sleep quality are considered to be one of the most destructive symptoms of these diseases and have a profound negative impact on the quality of life.

In addition, they are considered to be the main reason for sending patients with neurodegenerative diseases into residential care facilities.



Melatonin and cortisol rhythm

Disturbances in the circadian rhythm of the release of melatonin and cortisol in AD, PD, and HD have been recorded. What the two have in common is the flattening of the melatonin rhythm, so the normal nighttime peak is suppressed relative to a healthy, age-matched control.

A peak drop in nocturnal melatonin release has also been observed in individuals showing preclinical cognitive symptoms of dementia, and this drop appears to be positively correlated with the level of daytime sleepiness.

Changes in the cortisol release rhythm have also been observed, although these changes are different compared to melatonin. The normal cortisol rhythm rises in the early morning, the peak appears near waking, and the lowest point appears in the evening. Minor changes in this rhythm are observed in individuals suspected of Alzheimer’s disease or dementia.

In Parkinson’s disease and Parkinson’s disease, the daily pattern of cortisol release remains rhythmic, but the total daily amount of cortisol release is elevated. Core Body Temperature Rhythm The human core body temperature rhythm rises during the day, reaches its peak in the evening, then falls at night, and reaches its lowest point in the early morning.

Studies on individuals with Alzheimer’s disease have shown that the peak of this rhythm is delayed and its amplitude is reduced. In Parkinson’s disease, only the amplitude of the rhythm seems to be reduced.

This change was attributed to the decrease in peak body temperature relative to healthy age-matched controls. A significant decrease in the amplitude of the temperature rhythm was also recorded in the high-definition rodent model.



Emotion and behavior rhythm

According to reports, as neurodegenerative diseases progress, a rhythm of mood and mood swings will appear. This “sunset syndrome” includes patterns of increased anxiety, mood swings, and aggression that peak in the evening or evening.

This syndrome is not officially recognized as a clinical disease—in fact, the behavioral characteristics that it includes and whether the increased behavioral disorder during this time of day truly reflects a clinical phenomenon or mixed effects , Such as reporting deviations from caregivers.

However, many reports indicate that a small but significant proportion of Alzheimer’s patients do exhibit predictable circadian patterns of behavior and mood disorders, especially in those with severe symptoms.

The factors that lead to anxious behavior are not clear, but some evidence suggests that this pattern is not a direct consequence of sleep loss.


Neurodegenerative diseases and clock gene expression. Evidence from individuals with AD, PD, or HD and animal models of each disease state indicate abnormalities in the expression rhythm of bmal1 and per2. In Alzheimer’s disease, the change pattern of bmal1 gene expression is complex. In several brain regions and peripheral tissues, bmal1 mRNA expression remained rhythmic; however, compared with healthy controls, the temporal phase relationship between these tissues was different. In the pineal gland, the rhythm of bmal1, per1 and cry1 mRNA is lost.

In Parkinson’s disease, the amplitude of the bmal1 transcription rhythm in blood cells is reduced. In addition, the rodent model of Parkinson’s disease showed that the rhythmic per2 gene and PER2 protein expression were attenuated in several brain regions and peripheral tissues downstream of SCN control. For example, the loss of dopaminergic innervation in the striatum disrupts the rhythmic expression of PER2 protein in this area. Similarly, in rodent models of HD, the normal rhythm of per2 gene expression in central and peripheral tissues is disrupted



Does the FAUL TY biological clock cause neurodegenerative diseases?

In view of the prevalence of rhythm abnormalities in neurodegenerative diseases, circadian rhythm disorders are increasingly regarded as precursors of neurodegenerative diseases.

Consistent with this idea, some prospective studies have identified excessive daytime sleepiness, fragmentation of daytime activities (Tranah et al., 2011) and sleep behavior disorders; as Alzheimer’s disease, Parkinson’s disease related to dementia Independent predictors of disease and cognitive impairment.

As far as RBD is concerned, the vast majority of affected individuals appear to be at risk for Parkinson’s disease or related synucleinopathy, especially if they also exhibit additional non-exercise risk factors. The interruption of these circadian rhythms is the result of neurodegeneration affecting the brain and peripheral clock mechanisms, or is the endogenous clock dysfunction directly causing disease progression?

Obviously, the long-term disruption of normal circadian rhythms has various negative effects on health through mechanisms such as extensive effects on gene transcription and pro-inflammatory processes, which may aggravate the progression of these pathologies. However, many findings indicate that the circadian rhythm system may actually play a more direct role in the cause of neurodegenerative diseases.

For example, single nucleotide polymorphisms of bmal1 and per1 are associated with increased risk of PD. In addition, clock genes regulate the expression of other genes directly related to neurocognitive disorders such as Alzheimer’s disease. For example, the presenilin-2 gene, which regulates the level of beta amyloid peptide and is associated with familial early-onset Alzheimer’s disease, is expressed rhythmically in SCN.

In peripheral tissues, CLOCK:BMAL dimer regulates the expression of Presenilin-2 through transcription and post-transcriptional mechanisms.

These findings indicate a causal link between clock genes and the molecular factors that confer neurodegeneration risk. However, as far as we know, no experimental studies have shown that the manipulation of clock genes affects the expression of Presenilin-2 in the brain.

Although the evidence supporting this possibility is not entirely consistent, degenerative changes in the spinal nerves themselves may play a role in these disease states.

Some postmortem studies on brain tissues of patients with Alzheimer’s disease have shown that hypothalamic tissues (including cells in the spinal cord neural network) are missing, the expression of neuropeptides AVP and VIP is reduced, and the expression of melatonin receptor MT1 is reduced.

Compared with the control group, the spinal cord of the high-density rodent model reduced spontaneous discharge of nerve cells, but the number of SCN cells did not change. Although the coordinated SCN cell firing seems to be reduced as a normal part of aging, in the high-definition rodent model, this reduction occurs prematurely young (3 months).

Given that other hypothalamic structures degenerate in AD, PD, and HD, the structural changes of the master clock may be the result of a gradual process of tissue destruction in each disease state, rather than before the onset of the disease.

However, any dysfunction of the master clock may worsen the symptoms of these diseases through downstream effects on peripheral oscillators. Consistent with this view, the level of beta amyloid peptide in human cerebrospinal fluid is positively correlated with sleep fragments.

Convincing evidence suggests that the circadian system may contribute to neurodegenerative disease states by participating in the regulation of cell responses to oxidative stress. Oxidative stress is suspected to be a causal factor in neuronal damage, cell death, and mitochondrial dysfunction observed in AD, PD, and HD. Clock genes, such as bmal1, directly participate in the cellular antioxidant response through the downstream regulation of antioxidant response element transcription factors.

Compared with age-matched wild-type controls, rodents that selectively knock out bmal1 or period genes (per1 and per2) showed significantly higher rates of oxidative damage in their tissues. The circadian clock can also regulate oxidative stress through the rhythmic release of melatonin, which is an effective free radical scavenger.

These findings indicate that the abnormal operation of the molecular clock may create cellular conditions, and harmful by-products of metabolism and DNA replication may accumulate as a result, and mitochondrial damage may develop. In turn, these conditions may contribute to the pathogenesis of neurodegenerative disease states.


Circadian rhythm intervention for neurodegenerative diseases

If the circadian system is indeed a factor in neurodegenerative diseases, then therapeutic intervention for the circadian clock can alleviate symptoms and may even delay the progression of the disease itself. For this reason, many circadian therapies for Alzheimer’s disease, Parkinson’s disease and hemodialysis have been studied. One of the most commonly explored examples of such interventions is the use of bright light therapy.

Previous evidence suggests that older people in institutions may be exposed to bright light rarely every day, especially those with symptoms of severe dementia.

In view of the profound effect of light in regulating the timing of the master clock, many studies have evaluated whether regular bright light exposure has any beneficial effects on neurodegeneration or its symptoms. So far, the results have been mixed.

In general, timed lighting seems to moderately improve the regulation of the circadian rhythm system in patients with neurodegenerative diseases. With regard to Alzheimer’s disease, it has been reported that regular daily exposure to strong light has some positive but short-lived benefits for the consolidation of the activity rhythm of elderly people with Alzheimer’s disease and severe dementia.

In Parkinson’s disease, daily light improves the sleep/wake rhythm by reducing daytime sleepiness and increasing daytime activities. However, it is not clear whether timed exposure will reduce cognitive or motor skills decline over time. Although light exposure therapy has produced some short-term improvements in the activities of daily living of individuals with Alzheimer’s disease or Parkinson’s disease, there is not enough evidence to infer any long-term cognition or movement of this intervention. benefit.



Timed administration of melatonin has been used to study its therapeutic potential in Alzheimer’s disease, Parkinson’s disease and hemodialysis

As shown in in vitro and animal models, melatonin has antioxidant and apoptotic properties, and seems to prevent the formation of α-synuclein to aggregate the main protein component of Lewy bodies. However, in human randomized controlled clinical trials, the effects of melatonin supplementation on sleep quality and activity rhythm are inconsistent.

In Parkinson’s disease patients, daily dose of melatonin does not improve sleep quality, but it is related to the improvement of sleep self-report measures. In trials involving patients with suspected Alzheimer’s disease, moderate improvements in sleep quality (reduced sleep latency, improved sleep efficiency) and increased total sleep time were observed in some cases, especially when melatonin treatment was combined with daily When combined with bright light therapy.

However, other trials failed to determine any effects on the circadian rhythm of activity, sleep or cognitive symptoms. It has been reported that melatonin supplementation has a beneficial effect on behaviors related to sunset syndrome, but this effect has not been consistently found in randomized controlled trials.


The lack of evidence that timed light exposure and melatonin administration improves the non-circadian symptoms of AD, PD, and HD seems to disrupt the idea that the circadian system contributes to the etiology of these neurodegenerative diseases.

However, it is likely that some method inconsistencies in the experiment led to these uncertain findings. For example, studies evaluating light exposure have significant differences in the intensity of light used; exposure time; and clinical characteristics.

Similarly, the variability of dose, time of administration, and study sample characteristics may have contributed to inconsistent findings regarding the effects of melatonin. In addition, to our knowledge, no longitudinal studies have evaluated whether acyclic intervention can alleviate the long-term progression of neurodegenerative disease symptoms.

Careful consideration of the details of these methods and the inclusion of long-term follow-up intervals will facilitate the design of future studies. Since the circadian characteristics of neurodegenerative diseases may reflect the desynchronization of the downstream tissue oscillator controlled by the SCN from the master clock, another approach to therapeutic intervention involves the powerful influence of timed food delivery in circadian entrainment.

The circadian rhythm system maintains food sensitivity as a time cue during healthy aging. Given that timed food delivery is a very effective zeitgeber and does not exert its entrainment effect through SCN, timed eating or metabolic cues may help resynchronize interrupted circadian time. In fact, some evidence suggests that the food intake pattern of patients with suspected Alzheimer’s disease or related dementia changes as the disease progresses.

For example, compared with elderly people without AD symptoms, institutional elderly people with AD symptoms tend to consume less food in the afternoon and evening, and breakfast becomes the main meal that provides the maximum energy intake throughout the day.

Recent studies have shown that restricting eating time can relieve some of the circadian symptoms of neurodegeneration. Compared with the wild-type control group, in the R6 No. 2 rodent model, restricting food to the 6-hour window during the light phase restored the liver’s motor activity rhythm and changed the clock gene expression pattern.

Compared with the wild-type control group, the use of the dark-period restrictive feeding program also appeared to delay the development of the high-density phenotype of R6/2 mice and increase the core body temperature.

It would be valuable to use animal models of Alzheimer’s disease and Parkinson’s disease to further study the effects of time-restricted food.




In summary, more and more evidences strongly suggest the role of the circadian system in the pathogenesis and expression of AD, PD and HD.

Disruption of the normal rhythmic process is increasingly recognized as a characteristic of these disease states, and these disturbances can be used as early indicators of the development of pathology. At the molecular level, clock genes regulate many genes and biochemical processes that directly lead to neurodegeneration.

Although it is not clear whether the circadian rhythm system plays a causal role in the pathogenesis, further research may shed light on this relationship.

Advances in knowledge on this subject may promote the development of screening tools to identify individuals in the early stages of neurodegeneration and may open new areas of therapeutic intervention.

Given that the incidence of neurodegenerative diseases is expected to increase in the next few years, these advances will be timely and welcome.



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