Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin

Abstract

Alzheimer’s disease (AD) is associated with altered eating behavior and metabolic disruption. Amyloid plaques and neurofilament tangles are observed in many hypothalamic nuclei from AD brains. Some of these areas (suprachiasmatic nuclei, lateral hypothalamic area) also play a role in the regulation of the sleep/wake cycle and may explain the comorbidity of eating and sleep disorders observed in AD patients. Inadequate sleep increases the neurodegenerative process, for example, the decrease of slow-wave sleep impairs clearance of β-amyloid peptide (Aβ) and tau protein from cerebral interstitial fluid. Cerebrospinal fluid (CSF) melatonin levels decrease even in preclinical stages (Braak-1 stage) when patients manifest no cognitive impairment, suggesting that reduction of melatonin in CSF may be an early marker (the cause for which is still unknown) of oncoming AD. Melatonin administration augments glymphatic clearance of Aβ and reduces generation and deposition of Aβ in transgenic animal models of AD. It may also set up a new equilibrium among hypothalamic feeding signals. While melatonin trials performed in the clinical phase of AD have failed to show or showed only modest positive effects on cognition, in the preclinical stage of dementia (minimal cognitive impairment) the effect of melatonin is demonstrable with significant improvement of sleep and quality of life. In this review, we discuss the main aspects of hypothalamic alterations in AD, the association between interrupted sleep and neurodegeneration, and the possible therapeutic effect of melatonin on these processes.

Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

“…Under other conditions, melatonin has been shown to preferentially exert anti-inflammatory, antioxidant, and other beneficial actions in aging [10,26,70,74,93,94,95,96,97,98,392,393,394]. Concerning anti-inflammatory effects, melatonin suppresses various processes that lead to enhanced formation of reactive oxygen and nitrogen species and to proinflammatory signaling, as summarized in Section 2.…”

“…Circadian disruption, a major source of sleep disturbances, indicates that changes in melatonin secretion may be involved. In fact, melatonin has been recently shown to increase Aβ clearance [93,94]. Numerous other anti-amyloidogenic effects of melatonin have been also described and repeatedly reviewed [70,95,96,97,98].…”

Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus

“…Interestingly, AD patients show decreased melatonin circulating levels [78,79], and sleep disorders that enhance tau and beta-amyloid deposition and worsen memory impairment [80][81][82]. In this regard, if melatonin can scavenge free radicals to mitigate oxidative stress avoiding neuronal apoptosis and simultaneously preserve the integrity of the dendritic arbors, and also improves sleep-wake patterns [83,84], then aged population with reduced circulating levels of this indoleamine and sleep disorders might have increased vulnerability to suffer neurodegeneration after even a moderate pro-oxidant event. Furthermore, since melatonin induces neurogenesis, promotes survival of new neurons in the hippocampus [53,72,76,77], modulates overall neuroplasticity [75], and regulates main functions such as metabolism or sleep, low melatonin levels and/or a misalignment of its biosynthesis due to circadian disruption [72], could be an additional mechanism underlying impaired brain functioning and impoverishment of quality of life in AD patients.…”

Pathophysiology of Memory Inception and Retrogression and Clock Dependent Divergence in Cognizance

“…It has been reported that melatonin is attenuated during the ageing process and the patients with AD had a substantial reduction of this hormone. However, melatonin supplementation was found to minimize Aβ neurotoxicity and formation while enhancing cognitive efficiency [97][98][99][100][101][102][103].…”