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sleep dysregulation in Alzheimer's disease
There are at least three g protein-coupled receptors that effect sleep that are damaged in Alzheimer's disease: melatonin receptors, NPY receptors, and oxerin receptors. Here is some information on each.
The pineal hormone melatonin is involved in physiological transduction of temporal information from the light dark cycle to circadian and seasonal behavioural rhythms, as well as possessing neuroprotective properties. Melatonin and its receptors MT1 and MT2, which belong to the family of G protein-coupled receptors, are impaired in Alzheimer's disease (AD) with severe consequences to neuropathology and clinical symptoms. The present data provides the first immunohistochemical evidence for the cellular localization of the both melatonin receptors in the human pineal gland and occipital cortex, and demonstrates their alterations in AD. We localized MT1 and MT2 in the pineal gland and occipital cortex of 7 elderly controls and 11 AD patients using immunohistochemistry with peroxidase-staining. In the pineal gland both MT1 and MT2 were localized to pinealocytes, whereas in the cortex both receptors were expressed in some pyramidal and non-pyramidal cells. In patients with AD, parallel to degenerative tissue changes, there was an overall decrease in the intensity of receptors in both brain regions. In line with our previous findings, melatonin receptor expression in AD is impaired in two additional brain areas, and may contribute to disease pathology.
In conclusion, NPY participates in sleep regulation in humans, particularly in the timing of sleep onset and may as such play a role in the integration of sleep regulation, food intake and metabolism.
However, significant decreases in [3H]NPY receptor densities (Bmax) were found in temporal cortex (-43%) and hippocampus (-49%) in AD brains.
Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimer’s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD).
Three important points here: disrupted sleep has a negative effect on memory, learning, and behavior; many other g protein-coupled receptors are damaged by oxidation in Alzheimer's disease including receptors that affect the retrieval of short-term memory, smell, social recognition, and alertness, and certain antioxidants can partially restore the function of these receptors.
Clinical studies have shown that taking melatonin to fix disruptive sleep in Alzheimer's is ineffective. Maybe caused by dysfunctional receptors.
Lane, do you know of any antioxidant that can help restore the functions of the involved receptors?
This is an important observation followed by an important question. One of the few studies for the use of antioxidants to treat sleep disturbances in Alzheimer's disease is the following:
The average participant was 85.7 yr, 29% male, with a Montreal Cognitive Assessment score of 7.0. As expected, there was considerable variation in sleeping patterns across subjects. The total minutes of sleep per night with placebo oil was 408 minutes (sd=86). This significantly increased (p=.01) by 41 minutes (95% CI: 44.7, 38.35) during the week they received lavender. There was not a significant effect of time or the order in which oils were applied.
The use of lavender shows promise as a non-pharmacologic alternative for management of sleep disturbance in people with memory loss.
So if the melatonin receptors are disrupted....then MAYBE melatonin would help???
And yes, I get the clinical studies....BUT....
(Sorry if I can no be concise my thoughts, please bear with me)
I know for my granddaughter autism...they say that autistics do no make as much melatonin (which similar receptors disrupted)....and I know for fact that melatonin help my granddaughter in amazing ways....BUT...I have learned a few important points along the way.
MOST doctors rx 3-5 mg melatonin start with - but this WAY WAY more high than should be....and cause most kids have nightmares and feel bad (my guess is clinical study did same).
The body supposedly make 3 mg at dusk....and we have remember that the body making melatonin as well as what we take.
I found our best help was with 1mg melatonin.
I think it worth a try.
The question perhaps is can supplementation makeup for what the brain is not producing and releasing. Melatonin appears to work better for someone with mild cognitive impairment than with Alzheimer's disease. And it probably does help with autism, although dosing levels as you note are critical (nightmares are one of the main side effects of high doses of melatonin)
Melatonin is an antioxidant so supplementation may have some effect in terms of increasing the synthesis and release of melatonin itself.
Our study supports the view that the antioxidant and anti-inflammatory effect of melatonin is also correlated with the inhibition of peroxynitrite production and PARS activation. In conclusion, melatonin may be a novel pharmacological approach to prevent cell injury in acute inflammation.
And nitro-oxidative stress is likely the key overlap between Alzheimer's disease and autism
Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders respectively, with devastating effects not only on the individual but also the society. Collectively, a number of factors contribute to the expression of ASD and AD. It is of utmost curiosity that these disorders express at different stages of life and there is an involvement of certain susceptible genes. This genetic basis makes the background of common associations like memory deficits, cognition changes, demyelination, oxidative stress and inflammation, an integral part of both disorders. Modern technology resulting in genetically modified crops and increase in gadgets emitting electromagnetic frequencies have resulted in enhanced risks for neurological dysfunctions and disorders like ASD and AD. Subsequent advances in the psychological, pharmacological, biochemical and nutritional aspects of the disorders have resulted in the development of newer therapeutic approaches. The common clinical features like language impairment, executive functions, and motor problems have been discussed along with the patho-physiological changes, role of DNA methylation, myelin development, and heavy metals in the expression of these disorders. Psychopharmacological and nutritional approaches towards the reduction and management of risk factors have gained attention from the researchers in recent years. Current major therapies either target the inflammatory pathways or reduce cellular oxidative stress. This contribution focuses on the commonalities of the two disorders.
I have been taking montelukast (Singulair), a generic asthma attack prevention drug, for almost a year for early stage dementia. After the first week until now, I am completely back to normal - no extreme mental fatigue, no feelings of confusion, etc. My sleep is also much much better. I stopped having dreams many years ago. After taking this drug, my dreams have come back, and I am sleeping more deeply. I am now 69 and I feel twenty years younger. When I get up to go running in the morning, I feel better and my running is better.
The drug works by blocking potent inflammatory eicosanoids (cysteinyl leukotrienes) from entering cells in the brain and other organs and causing inflammation. I think that this drug reduces inflammation in a safe and effective way to improve your sleep and your health as you get older.