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   Melatonin in Alzheimer’s Disease   
      
      
   Li Lin,1,2,† Qiong-Xia Huang,3,† Shu-Sheng Yang,2 Jiang Chu,1 Jian-Zhi   
   Wang,1,* and Qing Tian1,*   
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   Abstract   
   Alzheimer’s disease (AD), an age-related neurodegenerative disorder with   
   progressive cognition deficit, is characterized by extracellular senile   
   plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary   
   tangles, mainly containing    
   the hyperphosphorylated microtubule-associated protein tau. Multiple factors   
   contribute to the etiology of AD in terms of initiation and progression.   
   Melatonin is an endogenously produced hormone in the brain and decreases   
   during aging and in patients    
   with AD. Data from clinical trials indicate that melatonin supplementation   
   improves sleep, ameliorates sundowning and slows down the progression of   
   cognitive impairment in AD patients. Melatonin efficiently protects neuronal   
   cells from Aβ-mediated    
   toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ   
   generation, but also arrests the formation of amyloid fibrils by a   
   structure-dependent interaction with Aβ. Our studies have demonstrated that   
   melatonin efficiently    
   attenuates Alzheimer-like tau hyperphosphorylation. Although the exact   
   mechanism is still not fully understood, a direct regulatory influence of   
   melatonin on the activities of protein kinases and protein phosphatases is   
   proposed. Additionally, melatonin    
   also plays a role in protecting the cholinergic system and in an   
   i-inflammation. The aim of this review is to stimulate interest in melatonin   
   as a potentially useful agent in the prevention and treatment of AD.   
   Keywords: Alzheimer’s disease, melatonin, tau hyperphosphorylation, beta   
   amyloid, antioxidation, cholinergic, neuroinflammation   
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   1. Introduction   
   Alzheimer’s disease (AD) is an age-associated neurodegenerative disease and   
   characterized by progressive loss of cognition and other neurobehavioral   
   manifestations. Pathological hallmarks of AD include extracellular senile   
   plaques (SP), mainly    
   consisting of β-amyloid (Aβ), and intracellular neurofibrillary tangles   
   (NFTs), mainly composed of abnormally hyperphosphorylated tau, a   
   microtubule-associated protein [1]. In spite of a large number of studies   
   undertaken, the etiology of AD is largely    
   unknown. Many mechanisms have been proposed, including genetic predispositions   
   (e.g., expression levels and subforms of presenilins (PS) and Apolipoprotein   
   (Apo) E), inflammatory processes associated with cytokine releasing, oxidative   
   stress and    
   neurotoxicity by metal ions [2–6].   
   Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan metabolite and   
   synthesized mainly in the pineal gland, has a number of physiological   
   functions, including regulating circadian rhythms, clearing free radicals,   
   improving immunity and generally    
   inhibiting the oxidation of biomolecules. Decreased melatonin in serum and   
   cerebrospinal fluid (CSF) and the loss of melatonin diurnal rhythm are   
   observed in AD patients [7–12]. Furthermore, the level of melatonin in CSF   
   decreases with the progression    
   of AD neuropathology, as determined by the Braak stages [12]. Melatonin levels   
   both in CSF and in postmortem human pineal gland are already reduced in   
   preclinical AD subjects, who are cognitively still intact and have only the   
   earliest signs of AD    
   neuropathology [8,12]. A strong correlation exists between pineal content and   
   CSF level of melatonin [8] and between CSF and plasma melatonin levels [7],   
   suggesting that a reduced CSF melatonin level may serve as an early marker for   
   the very first stages    
   of AD. In mammals, melatonin exerts some of its functions through two specific   
   high-affinity membrane receptors, melatonin receptor 1 (MT1) and melatonin   
   receptor 2 (MT2). Decreased MT2 immunoreactivity and increased MT1   
   immunoreactivity have been    
   reported in the hippocampus of AD patients [13,14]. Although the pineal gland   
   of AD patients has molecular changes, no changes in pineal weight,   
   calcification or total protein content have been observed [8,15]. It is also   
   shown that β1-adrenergic    
   receptor mRNA disappeared, and the activity and gene expression of monoamine   
   oxidase (MAO) were upregulated in AD patients, suggesting that the   
   dysregulation of noradrenergic innervations and the depletion of serotonin,   
   the precursor of melatonin, might    
   be responsible for the loss of melatonin rhythm and reduced melatonin levels   
   in AD [16]. Melatonin supplementation has been suggested to improve circadian   
   rhythmicity, for example, decreasing agitated behavior, confusion and   
   “sundowning”, and to    
   produce beneficial effects on memory in AD patients [17–21]. Therefore,   
   melatonin supplementation, with its marked low toxicity [22–24], may be one   
   of the possible strategies for symptomatic treatment.   
   In AD, Aβ is generally believed to play an important role in promoting   
   neuronal degeneration by rendering neurons more vulnerable to age-related   
   increases in levels of oxidative stress and impairments in cellular energy   
   metabolism [25]. As the major    
   microtubule-associated protein, tau promotes microtubule assembly and   
   stabilizes microtubules. Hyperphosphorylation will obviously reduce the   
   abilities of tau, which leads to cytoskeletal arrangement disruption [26,27].   
   The extent of neurofibrillary    
   pathology, and particularly the number of cortical NFT, correlates positively   
   with the severity of dementia [28]. As melatonin is able to improve some of   
   the clinical symptoms of AD, and the level of melatonin decreases dramatically   
   during AD, studies on    
   the relationship between melatonin and AD pathology will be helpful to assess   
   its potential in the prevention or treatment of AD. In this review, we will   
   address the role of melatonin in tau hyperphosphorylation and Aβ toxicity. As   
   cholinergic deficit    
   and inflammation are involved in AD pathogenesis, the protection of melatonin   
   on the cholinergic system and inflammation are also introduced. Each part is   
   described, from phenomenon observation to mechanism investigation and   
   speculation.   
      
      
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   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742260/?report=classic   
      
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