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Read with caution!

This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.

Beta amyloid (Wikipedia)

Aβ is the main component of amyloid plaques (deposits found in the brains of patients with Alzheimer’s disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[11] a protein fold shared by other peptides such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer’s disease.[12]

Researchers in Alzheimer’s disease have identified five strategies as possible interventions against amyloid:[26]

  • β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
  • γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
  • Selective Aβ42 lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions.
  • Immunotherapies. These stimulate the host immune system to recognize and attack Aβ or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.
  • Anti-aggregation agents[27] such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[28]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its agregation[29][30][31] This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer’s disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below).[32]. Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[33]

A 2009 report has just shown that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep.[32] The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production.[32] The report suggested that excessive periods of wakefulness (i.e. due to sleep debt) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer’s disease.[32] This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer’s disease.

Melatonin is also involved in circadian rhythm maintenance. Notably, melatonin has been connected with the “sundowning” phenomenon, in which Alzheimer’s disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer’s disease symptoms late in the day.[34] This “sundowning” phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

 

 

“Progressive disruption of the circadian rhythm of melatonin in fatal familial insomnia,” Portaluppi et. al., J Clin Endocrinol Metab (1994)

http://www.ncbi.nlm.nih.gov/pubmed/8175963

 

Melatonin (from Wikipedia):

Circadian rhythm disorders

Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPS than in people with insomnia.[17]

Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain’s own production accomplishes. This usage is now common in sleep and relaxation drinks.[18]

A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn’t cause sleepiness but, acting as a chronobiotic (affecting aspects of biological time structure),[19]advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and a small oral dose of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.[20]

The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent.[21] Melatonin is an anti-oxidant and suppressant of tumor development that is produced at night; when someone works in artificial light, they generally have lower melatonin and may be more likely to develop cancer. Melatonin supplements may simulate the melatonin production at different times that does not occur during regular sleeping hours for people who work night shifts.[22]

Learning, memory and Alzheimer’s

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[23] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). The first published evidence that melatonin may be useful in Alzheimer’s disease was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.[24] Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation ofneurofibrillary tangles, the other neuropathological landmark of Alzheimer’s disease.[25]

Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer’s disease.[26] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer’s, adversely affecting their bodies’ production of melatonin. Those Alzheimer’s patients with this specific affliction often show heightened afternoon agitation, called sundowning, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[27]