Enhance Aβ protein and aluminum clearance: Sleep does more than relieve the feeling of sleepiness. It has been found that both natural sleep and anesthesia induced sleep are associated with a 60% increase in the interstitial space in the brain. The interstitial space is the space between neurons. It is filled with interstitial fluid. This increased space results in a significant increase in convective exchange of cerebrospinal fluid with the interstitial fluid. This convective flux has been shown to increase the rate of beta-amyloid (Aβ) protein clearance during sleep as compared to the rate of Aβ clearance while awake517.
Aβ protein as oligomers and plaque in the brain is complexed with metal ions including aluminum. Purging these metal laden Aβ protein complexes from the brain is an excellent way to lower levels of accumulated aluminum in the brain137. Factors that slow the rate of clearance of beta-amyloid (Aβ) from the brain account for its’ build- up over time. Enhancing the rate of clearance will postpone the onset of AD and possibly prevent AD.
Consolidate Memories: Sleep has also been implicated in the off-line reprocessing of recently acquired memory. This process is called memory consolidation. The neurochemical mechanism for memory consolidation in mice has been found to involve a molecular cascade ending in the production of a molecule named P-CREB, that increases the transcription of genes responsible for brain derived neurotrophic factor (BDNF) production 179,180,518,519. Rapid eye movement (REM) sleep has been found to speed up this molecular cascade in the mouse brain increasing P-CREB production520and improving long term memory, brain plasticity, and learning181,182.
Lower Aβ Peptide and Plaque Levels: By increasing P-CREB production, REM sleep also increases the transcription of genes responsible for somatostatin production179,180,518,519. There is an inverse relationship between P-CREB levels and Aβ peptide in mouse brain. This is probably due to P-CREB increasing somatostatin levels that thereby increasing neprilysin activity that in turn lowers Aβ peptide and plaque levels. Therefore REM sleep can postpone the onset of AD by increasing both P-CREB and somatostatin levels in hippocampal neurons103.
The beneficial effects of REM sleep can be negated by aluminum accumulating in the brain. It has been found that aluminum chloride in the diet of neonatal and postnatal rats inhibits P-CREB production by modifying the calcium/calmodulin complex520. This in turn lowers both hippocampal BDNF and somatostatin production resulting in long term memory impairment, spatial learning impairment, and Aβ peptide accumulation101,102.
Sleep Better with Daytime Solar or Blue Lighting: Orexin (a.k.a. hypocretin) is a neurotransmitter produced in the hypothalamus by 10,000 to 20,000 orexin neurons that extend over the entire brain and spinal cord. Orexin promotes wakefulness and regulates arousal, wakefulness, and appetite. Circadian rhythms are controlled by high levels of orexin during the day and low levels at night. In AD, dysregulation of the orexinergic system results in too much orexin in the cerebrospinal fluid521. In mild and moderate AD this dysregulation causes more awakenings and less REM sleep during the night resulting in greater than normal daytime sleepiness. This condition is correlated with cognitive impairment in AD146 possibly due to more Aβ protein accumulation and less Aβ clearance at night521.
Melanopsin, like orexin, promotes wakefulness and is involved in neuronal communication with the brain’s clock. The brain’s clock controls circadian rhythms and is called the suprachiasmatic nucleus. Melanopsin, one of the three light-sensitive retinal opsin proteins in the human eye, is found in neurons in the retina called intrinsically photosensitive retinal ganglion cells (ipRGCs). Blue light photostimulates melanopsin in ipRGCs linked neuronally to the brain’s clock522. The solar spectrum reaching the earth has a strong blue component. Therefore exposure to solar lighting during daytime hours is recommended to photostimulate melanopsin maintaining daytime wakefulness. This daytime wakefulness helps to maintain circadian rhythms and a good night’s sleep resulting in less Aβ protein accumulation and more Aβ clearance.
Aβ oligomers complexed with aluminum compared with other metals are less prone to aggregate and are sufficiently small to scatter blue light522. The percentage of blue light being scattered to total blue light entering the eye increases as Aβ oligomer concentration rises in the retina523. Also ipRGC degeneration has been recently observed in AD patients524. Therefore some patients with AD need to see more blue light to compensate for both scattering and degeneration in order to maintain circadian rhythm. Thus it is not surprising that using lights with enhanced output in the blue spectral region during the day allows some elderly patients with AD to sleep better at night525. Moderation is called for as long-term blue light exposure can cause retinal damage. Mixing exposure to both solar and blue lighting during the day is a good compromise.