Alzheimer_s disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best-known hypothesis to explain AD is that which involves the role of the accumulation of amyloid-b peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti-inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD.

Is it just a coincidence that while melatonin declines with age, the probability of experiencing AD grows? New findings on CSF flow, possibly moving from the choroid fissure into the ventricular system, could help to explain why melatonin is found in higher concentration in the CSF than in simultaneously sampled blood. Thus, neural tissue in contact with the ventricular system via hypothetical choroid plexus portals would have high levels of cellular melatonin [477]. A CSF deficiency of melatonin has been demonstrated to precede clinical symptoms of AD [22, 265] and, the loss of this lipophilic antioxidant normally concentrated in the ventricular CSF exposes highly active and vulnerable brain tissue to self-generated oxygen radicals. Melatonin_s more common indication in patients with AD is sleep regulation because sleep disruptions, nightly restlessness, and sundowning are frequently observed in elderly and particularly in patients with AD [44]. This is related to decreased levels of both melatonin [415] and melatonin receptors in the SCN [478]. It has also a potential to treat mood disorders [30, 43], commonly associated with AD [28, 30]. By taking into account the most compelling hypotheses trying to explain the cellular and biomolecular alterations in Alzheimer_s disease, however, a growing body of evidence supports the protective role of melatonin, exceed ing the above-mentioned conventional uses. Thus, melatonin has a role in each of the different reviewed hypotheses: (i) it prevents amyloid overproduction, (ii) it reduces hyperphosphorylation of tau [15, 166], (iii) it is an antioxidant and free radical scavenger, (iv) it modulates proinflammatory processes, (v) it works well as an anticholinesterase agent, (vi) it prevents mitochondrial damage and the apoptotic phenomena related with AD, (vii) it may impair calcium-dependent toxicity, (viii) it reduces insulin resistance as well as glucose transport, and finally (ix) it is able to maintain the integrity and functionality of cellular membranes, thanks to its ability to interact with lipids or against their neuroinflammatory or proapoptotic signals when the lipid balance becomes affected. The functional translation of these biomolecular effects has been also well documented. MT2 receptor-deficient mice undergo impairment of synaptic plasticity and learning- dependent behavior, suggesting that MT2 receptors participate in hippocampal synaptic plasticity and in memory processes [299]. Also relevant are the protective effects of melatonin on cognition in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function, as observed in a transgenic model of AD [20]. It is worth remembering the increased melatonin 1a-receptor immunoreactivity in the hippocampus of patients with AD, which may be a compensatory response to impaired melatonin levels [417]. It is also true that in transgenic animals, additionally exposed to aluminum for months (aluminum has been circumstantially linked to AD [16, 479, 480]), melatonin did not ameliorate the behavioral effects [21] even though they did respond well to the antioxidant actions of [92]. Limited or even null results in memory performance or other high mental functions using melatonin have been observed in some clinical trials [11]. However, these changes are associated with the loss of brain cells. The greater the loss of brain cells, the more severe the deterioration in high mental functions, and no drug exists that is capable of regenerating lost neurons. Once the brain tissue has degenerated, there is just a little chance of recovering [176]. There are several concerns about melatonin. From a cellular, basic perspective, we find a single report where melatonin reportedly worsens the neurodegenerative pathology. It is a rotenone-induced Parkinson_s diseasespecific model, where melatonin not only failed to impair neuronal degeneration but potentiated neurodegeneration [19]. However, synergistic effects of melatonin against MPTP-induced mitochondrial damage and dopamine depletion have been also reported [481]. Otherwise, the evidence indicating the protective role of melatonin on mitochondria within CNS is vast [239, 342–346, 348–350, 352, 353, 355, 359]. On the other hand, there are several clinical concerns. One refers to dose and side effects. In a few isolated studies, melatonin has been related to sleepiness, dizziness, headaches, nightmares, confusion, sleepwalking, daytime sleepiness, and abdominal discomfort, even though some results deserve a re-analysis. For example, using a high dose of melatonin (20 mg/kg) in mice undergoing electroconvulsive stimulation, a strong long-term memory deficit was attributed to melatonin [482]. However, it was not clear what caused the memory impairment actually, because the electroconvulsive stimulation has been often related to memory impairment by itself; and not only in rodents but in humans (reviewed in [483]). On the other hand, not in rats but in epileptic children, a randomized, double-blind, placebo-controlled trial demonstrated that melatonin improved cognitive and social function as well as emotional well-being and behavior [484]. It has been also reported that ramelteon, a synthetic melatonin derivative, administrated prior to a short (2 hr) evening nap, impairs significantly neurobehavioral performance for up to 12 hr after awakening [485].However, a 2-hr nap is not a short nap; naps longer than 30 min have been largely associated with a loss of productivity and sleep inertia [486]. Thus, probably ramelteon was not responsible for a low neurobehavioral performance, but the long nap by itself. Melatonin doses ranging from 3 to 6.6 g/day for more than 30 days were administrated in patients with Parkinson _s disease, and the number of collateral effects, such as headache, somnolence, or abdominal cramps, were isolated, with melatonin being _remarkably well_ tolerated [487]. More severe collateral effects have never been observed. In fact, doses up to 800 mg/kg failed to produce death in mice [488]; indeed, no lethal dose of melatonin has been established overall; melatonin has been repeatedly shown, at any dose to be free of significant side effects. Other concerns go in the opposite direction: melatonin_s extremely short half-life in the circulation, a question that have led to the development of synthetic melatonergic drugs with substantially longer half-life than melatonin [489]. It should be noted however that the short half-time of melatonin in the blood does not necessarily translate into a short half-life within the cells. This review underlines the potential of melatonin to slow the progressive deterioration of AD brain, in light of the known hypotheses that attempt to explain the neurodegeneration. As observed in AD models and based on a multitude of experimental results, melatonin benefits may well stem from actions that exceed its well-known antioxidant properties. Unfortunately, while there are a number of well-founded hypotheses, the real cause of neurodegeneration in AD is still unknown. Very likely, there are many contributing causes to this highly complex disease.

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