Melatonin in Synaptic Impairments of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.

Keywords

Alzheimer’s disease amyloid-β melatonin melatonin receptors synapse

MELATONIN AND ITS RECEPTORS IN ALZHEIMER’S DISEASE

Melatonin, N-acetyl-5-methoxytryptamine, is synthesized from tryptophan. Under the catalysis of tryptophan hydroxylase, tryptophan becomes 5-hydroxytryptophan which is converted into serotonin by aromatic amino acid decarboxylase. By arylalkylamine N-acetyltransferase (AANAT), serotonin is converted to N-acetylserotonin, which is then transformed into melatonin by hydroxyindoleO-methyltransferase (HIOMT). The pineal gland is the major organ where this endogenous small lipophilic indoleamine is synthesized and secreted at night under normal light/dark conditions. Some extra-pineal organs such as brain, bone marrow, gut, immune system cells, airway epithelium, and skin were also reported to produce and release melatonin [1]. The rhythm of melatonin secretion is generated by the suprachiasmatic nuclei (SCN), which is considered to be the self-sustained master circadian pacemaker and coordinates circadian rhythms by neuronal and/or hormonal pathways [2]. The average levels of peripheral melatonin of a human adult at daytime and nighttime are approximately 10 pg/mL and 60 pg/mL, respectively [3]. Melatonin secretion declines with age [4, 5]. In humans, melatonin starts to be secreted at six months after birth and it reaches the maximum level between the third and sixth years of life when the typical diurnal rhythm of secretion appears. A marked decrease in melatonin secretion is noted during sexual maturation and the striking decrease in daily melatonin synthesis can be observed at 40–50 years of age. After age 70, the diurnal rhythm of melatonin secretion practically disappears in most individuals [6]. Melatonin has multiple biological activities including neuroprotection, anti-inflammatory, anti- nociception, anti-depression, anxiolytic, regulating locomotor activity, modulating pain, reducing blood pressure, retinal protective, vascular protective, anti-tumor and antioxidant effects [1].

Physiologically, melatonin acts mainly by the following ways, including binding to melatonin receptors in plasma membrane, binding to intracellular proteins such as calmoduline, binding to orphan nuclear receptors, and anti-oxygenation [7]. In mammals, 5 types of melatonin receptors have been found: I) Melatonin receptor type 1a (Mel1a, also named MT1). MT1 receptor locates on the cell membrane and is found in the skin, brain, cardiovascular system, immune system, ovary, testes, liver, kidney, adrenal cortex, placenta, breast, retina, pancreas and spleen [8]. II) Melatonin receptor type 1b (Mel1b, also named MT2). MT2 receptor is also at the cell membranes and expressed in the immune system, brain, pituitary gland, retina, blood vessels, testes, kidney, gastrointestinal tract, mammary glands, adipose tissue and skin [9]. III) Quinone reductase 2 enzyme (NQO2, or MT3). MT3 receptor, a detoxification enzyme, exists in liver, kidney, heart, lung, intestine, muscle and brown fat tissue [7]. IV) Retinoid-related orphan nuclear hormone receptors (RORs). RORs are found in immune system, brain, liver, kidney, retina, as well as lung [10], they regulate the expressions of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expressions of downstream (metabolic) genes. RORα, which is expressed in neuron and astrocyte, but not in microglia, plays a critical role in the development of the cerebellum [11]. Both RORα and RORβ are required for the maturation of photoreceptors in the retina, and RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes [10]. V) G protein-coupled receptor 50 (GPR50). GPR50 is located in brain and periphery. Its natural ligand has not been defined yet. GPR50 does not bind to melatonin, however, it dimerizes with MT1 and inhibits the melatonin signal [11]. Among these receptors, MT1 and MT2 have been widely studied. In SCN of human brain, the number of MT1 positive neurons decreases with aging [12, 13]. Age-related declines in MT1 mRNA levels in the liver, spleen, kidney and heart of rats [13], as well as the SCN of C3H/HeN mice [14], and the age-related decreased mRNA levels of MT2 in the kidney, spleen, liver and heart of rats [13] were reported. Gerbil has the lowest MT2 level at young adult stage and the highest MT2 level at aged stage in the hippocampus [15]. In the thymus of 12-month-old rats, the levels of MT1 and MT2 receptors were significantly higher, however, MT1 protein expression maintained unchanged with aging [13]. Therefore, cerebral melatonin receptors might have region-specific differences during aging. Alzheimer’s disease (AD) is an age-related neurodegenerative disease, which is pathologically characterized by the extracellular amyloid-β (Aβ) plaques, the intracellular neurofibrillary tangles (NFTs), neuronal death, and synaptic loss. Declined melatonin, especially the nocturnal levels, in the pineal gland, cerebrospinal fluid (CSF), plasma, and urine as 6-hydroxymelatonin have been reported even more obvious in the patients with AD [16 –19]. The decreasing of melatonin in the blood and CSF has been reported to parallel the progression of neuropathology in AD brain, as determined by the Braak stages [20 –22], and CSF melatonin levels decrease even in preclinical stages while no cognitive disorder is presented [20, 21]. MT1 and MT2 receptors are both decreased in the pineal gland as well as pyramidal and non-pyramidal cells of cortical layers II to V [23]. MT1 in the SCN was even more strongly diminished in the late neuropathological stages of AD (Braak stages V-VI), but not in the early stages (Braak stages I-II) [12], and MT2 in the hippocampus were dramatically reduced [24]. Intriguingly, higher level of MT1 was detected in hippocampal arteries of AD brain [25]. MT2 was observed localized to pyramidal and granular neurons of the hippocampus in AD patients and controls, but the immunoreactivity intensity of MT2 in single cell and the number of MT2 immunoreactive neurons were significantly reduced in AD [24]. Similarly, the overall intensity of MT2 staining was clearly decreased in the retina, particularly at the level of ganglion and bipolar cells in the inner nuclear layer, the inner segments of the photoreceptor cells [26]. Traumatic brain injury (TBI), a risk factor of AD, resulted in lower levels of MT1 and MT2 in the frontal cortex and hippocampus of rats [27]. The diminished levels of melatonin are suggested to be an early marker for the very first stage of AD [20, 21], and melatonin supplement appears to be effective and safe in retarding the cognitive deficits progression in patients with AD [28, 29]. All these reports indicate a very close correlation between the progress of AD dementia and the decline of melatonin and its receptors.

SYNAPTIC IMPAIRMENTS IN AD BRAIN

Loss of synapse is regarded as one of the earliest signs of AD which triggers dementia [30]. Synapse is the specialized structure propagating electrical or chemical signals from one neuron to another, and synaptic plasticity is a critical phenomenon ensuring acquire and store new information. Although the formed memory is thought to be stored in the neocortical areas, memory consolidation is sensitively dependent on the integrity of hippocampus [31]. Long-term potentiation (LTP) is a synaptic enhancement that follows brief, high-frequency electrical stimulation in the hippocampus and neocortex in the efficacy of synaptic transmission [32, 33]. Hence, the associative and input-specific synaptic plasticity such as LTP and its counterpart long-term depression (LTD) is thought to underlie cellular correlates of learning and memory.

In AD, synaptic changes are present years prior to serious neuronal degeneration [30, 34]. Individuals with early AD had significantly fewer synapses than mild cognitive impairment, or no cognitive impairment [35], and the memory impairment correlates better with synaptic dysfunction [34]. Impairments in LTP have been reported in most transgenic AD models, such as Tg2576, 3xTg, PDAPP, and 5xFAD mice [36 –41], and deficits in LTP-like cortical plasticity have been reported in mild-to-moderate AD patients [42, 43]. As binding to synaptic sites [44] and reducing the density of spines observed in various AD models [45 –54], soluble oligomers of Aβ (Aβo) was regarded as one principal factor causing synaptic impairments in AD [55]. There are mainly 3 types of synapses contributing to the synaptic strength, namely glutamatergic, GABAergic, and dopaminergic synapses. The upstream mechanisms of synaptic impairments in AD are still not clarified although Aβ was reported widely linked.

Glutamatergic synapses in AD brain

Glutamate is the most abundant excitatory neurotransmitter. Its receptors are divided into two categories, the ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxa-zole propionic acid receptors (AMPARs), kainate receptors (GluKRs), and delta receptors (GluDRs) are the 4 subtypes of iGluRs. mGluRs indirectly modulate postsynaptic ion channels, consisting of G-protein coupled receptors (mGluR1-8).

In AD brain, excessive Aβ which inhibits LTP [56] and facilitates the induction of LTD [57], disrupts excitatory synaptic transmissions and plasticity, mainly by the dysregulation of the NMDARs and AMPARs [55 , 58–60] and the blockade on synaptic glutamate recycling [57 , 62]. Besides triggering NMDA-mediated Ca^2 + influx and excitotoxicity in the postsynaptic neurons [63, 64], Aβ could interact with NMDARs and reduce the location of NMDARs on the surface by endocytosis [65 –67]. Aβ also binds the calcium-permeable α7 nicotinic acetylcholine receptors (nAChRs) with high affinity [68]. This interaction is thought to contribute to the internalization of NMDARs through a calcineurin-dependent pathway [67, 69]. Additionally, Aβ was reported to induce the internalization of AMPARs and impede trafficking of AMPARs towards membranes [70]. Aβo was found to bind to cellular prion protein (PrP^C) with high affinity [71] and AD brain contains PrP^C-interacting Aβo and Aβ-PrP^C complexes [72 –74]. PrP^C is required in the inhibition of Aβ on synaptic plasticity [72 –74]. mGluR5 was found as a receptor for Aβo-PrP^C [59]. Aβo-PrPC can drive mGluR5-dependent calcium mobilization. Inhibition of mGluR5 prevents Aβ induced LTP impairment, spine loss, and cognitive deficits in AD mouse models [75]. Aβ was found to block glutamate reuptake by inhibiting both neuronal and glial glutamate transporters and altering glutamate recycling at the synapse [57 , 76], which contributes to an elevated level of extracellular glutamate [77, 78]. Elevated extracellular glutamate might lead to LTP inhibition [56], LTD enhancement [79] and neuronal death [79] through activating the extrasynaptic NMDARs. Therefore, decrease of the extracellular glutamate level was reported to be able to restore the Aβ-induced LTP damage [76].

Pathologic tau also plays an important role in the synaptic impairment of AD [80]. In the total synaptosomes isolated from rat brains, tau has been detected and the interaction of endogenous tau with synaptic proteins is regulated by NMDAR-dependent tau phosphorylation [81]. Additionally, tau in synapses also interacts with postsynaptic density protein 95 (PSD-95) and NMDARs. It is accepted that tau is essential for NMDA-dependent LTP and AMPA-dependent LTD, as data shown in tau knockout mice [80, 82]. In THY-Tau22 transgenic mice, a murine tauopathy model with normal LTP that expresses double-mutated 4-repeat human tau [83], the LTD impairment which paralleled with the progression of tauopathy and memory deficits was reported [84, 85].

GABAergic synapses in AD brain

In hippocampus, approximately 90% of neurons confer excitatory glutamatergic neurotransmission, and the remaining 10% are inhibitory, of which the majority are the neurons utilizing γ-aminobutyric acid (GABA). GABA has two modes of release, phasic and tonic [86]. The phasic release is mediated by synaptic vesicles in GABAergic neurons, and the tonic release is a sustained form of release and originated from glial cells [87, 88]. The actions of GABA are mediated by 3 distinct receptor subfamilies including GABA_A, GABA_B and GABA_C/GABA_A - ρ [89]. Both GABA_A and GABA_C receptors are ligand-gated chloride channels, whereas GABA_B receptors are G-protein coupled metabotropic receptors.

The processes of learning and memory require a balance of activity between excitatory and inhibitory neuronal network. Early studies concluded that GABAergic neurons and receptors appear more resistant to AD pathology, with only modest loss in AD [90]. However, this statement has been challenged recently [91]. In the temporal cortex of AD patients, a 33% decrease of GABA was observed [92]. The decreased GABA was also observed in the CSF of AD patients and normal old populations [93 –95]. In the hippocampus of aged Fischer 344 rats, the significant decrease of GABAergic interneurons is one of the conspicuous alterations [96]. Human amyloid precursor protein (hAPP) transgenic mice with high Aβ level showed an increased GABAergicneurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission [97]. In hippocampus of APP/PS1 (Presenilin-1, PS1) and 5xFAD mice, more astrocytes were found activated and these reactive astrocytes abundantly produce and release inhibitory GABA gliotransmitter. Normally astrocytes in wild type mice show minimal GABA immunoreactivity [98, 99] while in APP/PS1 mice, Aβ may stimulate the astrocytic GABA synthesis and release [99]. The hyperphosphorylated tau also has influences on the GABAergic synapses. In tau P301L mice with hyperphosphorylated tau, the GABAergic neurons were observed hyperactivated, leading to an increased GABA level in the brain [99]. GABA interneurons are important in regulating the activation of excitatory network prominently by GABA_A receptor-mediated inhibition. GABA_A receptor antagonist picrotoxin was demonstrated to prevent LTP deficits in an animal model of AD [100]. Pharmacological studies indicate that α5 subunit of GABA_A receptor is very abundant in hippocampus and is a key subunit involved in learning and memory [101, 102].

Dopaminergic synapses in AD brain

Dopaminergic neurons are mainly in the retrorubral field, the substantia nigra pars compacta (SNc), and the ventral tegmental area (VTA). There are 4 major dopaminergic pathways, including the mesolimbic pathway, the mesocortical pathway, the nigrostriatal pathway, and the tuberinfounibular pathway. The former two pathways are also named meso-cortico-limbic pathway. SNc gives rise to the nigrostriatal pathway, targeting the medium spiny projection neurons of the caudate and putamen nuclei. VTA delivers the meso-cortico-limbic pathway, targeting hippocampus, cerebral cortex and the nucleus accumbens. Pathological alterations of the meso-striatal pathway are generally associated with the development of extrapyramidal motor deficits, while the meso-cortico-limbic pathway is responsible for cognitive and behavioral signs. Dopamine (DA) receptors have been devided into 2 types, D1 and D2. The former comprises D1 and D5 receptor subtypes, which plays important roles in spatial learning and memory processes [103].

DA is a modulator of synaptic plasticity and a major determinant of memory encoding in the dorsal hippocampus [104, 105]. During aging, decreased DA, D1 and D2 receptors [106], and reduced DA transporters in caudate putamen, hippocampus and frontal cortex were observed [107, 108]. During the progress of AD, 35–40% of the patients present extrapyramidal signs [103] and reduced DA levels were detected in several postmortem brain regions including globus pallidus, putamen, nucleus amygdalae, nucleus caudatus, substantia nigra, gyrus cinguli and raphe [109]. The nigro-striatal, meso-striatal and meso-cortico-limbic pathways were reported to be involved in the AD progression [110]. Neurons in the nigrostriatal pathway presented NFTs, Aβ deposition, neuronal loss and decreased DA level as well [110]. Moreover, the restoration of DA transmission was demonstrated to participate in memory and learning in a mouse model of AD [111]. In APP/PS1 mice the dopaminergic pathology and Aβ deposition were closely related [112]. Degeneration of VTA dopaminergic neurons at pre-plaque stages contributes to memory deficits and the dysfunction of reward processing [113]. In Tg2576 mice, an age-related dopaminergic neuron loss in the VTA at pre-plaque stages was reported, and the progression of the dopaminergic neuron loss was correlated with synaptic impairments in CA1 [113]. Additionally, marked reductions at both D1 [114] and D2 [115] receptors have been observed in prefrontal cortex and hippocampus of AD patients. Activation of D1/D5 receptors prevents pathological changes in the composition and function of synapses induced by Aβo [116].

MELATONIN IN LTP MODULATION

The levels of melatonin in the brain ventricles were found 75-fold higher than the peripheral plasma [117 –119]. Hippocampus is very close to the ventricles [120, 121] and has 3 types of receptors of melatonin, MT1, MT2 and GPR50 [24, 122]. Thus, melatonin regulates memory formation by acting directly on the hippocampal neurons involved in memory acquisition and consolidation as previously reviewed [123, 124]. It is reported that hippocampal synaptic plasticity may be constrained by melatonin in hippocampus slices from mice through a regulation mediated by MT2 receptor on the adenylyl cyclase/protein kinase A (AC/PKA) pathway [125]. Melatonin is secreted at night and may maintain the levels of AC/PKA restrained during the rodents’ active phases. Thus, melatonin might constrain synaptic plasticity so that the formation of LTP is restricted to specific synaptic connections [125]. Another study showed the LTP inhibition of melatonin is due to the action of melatonin on the postsynaptic nitric oxide (NO) signaling pathway [126]. Some researchers reported that melatonin significantly alters the synaptic transmission and LTP in the CA1 region but has only modest actions in CA3 [127]. 0.1 mM melatonin blocked LTP, while 1 mM melatonin also depressed the field excitatory postsynaptic potentials (fEPSPS) at CA1. However, neither 0.1 nor 1 mM melatonin altered the fEPSP in CA3, whereas both concentrations only slightly reduced LTP [127]. Therefore, melatonin might have restrictions on LTP in physiological conditions. Further, melatonin might exert enhancements on LTP and synaptic transmission in pathological conditions. Melatonin has been reported to enhance the firing rate of action potentials and promote synaptic transmission in the CA1 neurons of brain slices [119]. And the chronic melatonin treatment could reverse Aβ_1 - 42 or Aβ_31 - 35 induced impairments in LTP induction [128]. In Ts65Dn mice, the most commonly used model of Down syndrome (DS), melatonin administration reduced synaptic inhibition by increasing the density and/or activity of glutamatergic synapses in hippocampus and a full recovery of hippocampal LTP [129]. Impaired hippocampal LTP in MT2 receptor deficient mice was reported, indicating that MT2 receptor participates in hippocampal synaptic plasticity and memory processes [130]. Induction of LTP is normally dependent on postsynaptic Ca^2 + influx after the activation of NMDARs. Melatonin increases NMDAR subunits 2A (NR2A) and 2B (NR2B) levels in rat hippocampus [131]. By increasing the levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and BDNF in cerebral cortex and hippocampus, melatonin restrained the cognitive deficits induced by sleep deprivation [132]. BDNF impacts synaptic plasticity by improving the efficiency of synaptic transmission via the activation of CaMKII in hippocampus [133].

The stabilization of synaptic structures by melatonin is critical for memory acquisition and consolidation. It is showed that melatonin promoted neurite outgrowth by inducing tubulin polymerization and microfilament redistribution [134]. Melatonin was reported benefit to the formation of synapses by increasing a presynaptic protein, synaptophysin, which is normally used to determine the number of synapses [135]. Melatonin is involved in dendritic structure in diurnal changes of hippocampal neurons in Siberian hamsters [136]. It was found that high levels of melatonin in CSF during night increased the number of neuronal dendrites as well as their complexity, length, and thickness [137]. Wild type mice treated with melatonin also leaded to a greater complexity of the dendritic structures [138]. In the ovariectomized mice melatonin could stimulate the maturation of spines and recover the dendritic spine density [139]. Actually, both chronic [138, 140] and acute melatonin treatments [137] could induce the dendrite development and spine formation inneurons.

An interesting study confirmed the location of MT1 receptor in presynaptic membranes and MT1 is a part of the presynaptic protein network in hypothalamus, hippocampus, striatum and cortex [141]. The strong physical association between MT1 receptor and presynaptic proteins such as synapsin, synaptosomal-associated protein 25 (SNAP25), Munc-18 and voltage-gated Cav2.2 channels was demonstrated in this study [141]. It has been reported that MT2 receptor activates Akt/GSK-3β/CRMP-2 signaling and is necessary and sufficient to mediate the functional axonogenesis and synaptic formation in central neurons [142]. And MT2 deficient mice, but not MT1 knockout mice, expressed a phenotype relevant to AD, including impaired learning and/or memory as well as the reduction of LTP maintenance [130]. However, another study reported that the knockout mice lacking both MT1 and MT2 receptors (MT-KO mice) had significant well cognitive performance in the Barnes Maze and the Y-Maze and an enhancement of LTP in the hippocampus slices [143]. GPR50 is widely present in the whole brains in adult mice including postsynaptic density fraction, the overexpression of GPR50 increased neurite length as well as filopodia- and lamellipodia-like structures in differentiated Neuroscreen-1 cells [144]. It has been demonstrated that melatonin receptor agonists (ramelteon, a novel clinically available agonist for MT1 and MT2 receptors) could enhance the expression of BDNF [145], which potentiates the dendritic outgrowth [146].

MELATONIN IN TRANSMISSIONS OF GLUTAMATERGIC, GABAergic, AND DOPAMINERGIC SYNAPSES

Melatonin induced an increase in the glutamatergic synaptic transmissions in the medial lateral habenula of rats which was blocked by the competitive MT1 /MT2 receptor antagonist luzindole [147]. A study supported that melatonin inhibits the voltage-sensitive Ca^2 + channel-mediated neurotransmitter release [148]. Melatonin (100μM) inhibits excitatory synaptic transmission of the hippocampal Schaffer collateral pathway with the decrease in basal synaptic transmission [148]. Melatonin is particularly involved in the inhibition of NMDARs in rodents. Melatonin could bring down calcium influx through modulating the conductance of voltage-gated Ca^2 + ion channels and thereby antagonize the effects on NMDARs [149, 150]. By activating the MT1 receptor, melatonin could modulate AMPAR-mediated glutamatergic transmission; a higher (micromolar) concentrations suppressed the glutamate currents, which could not be blocked by luzindole, suggesting that this effect of melatonin was unlikely mediated by the MT receptor [151]. Elevated levels of the post-synaptic GluR1 in the frontal cortex and reduced levels of glutamate decarboxylase 67 (GAD1), the key GABA-synthesizing enzyme, in the frontal cortex and hippocampus were observed in MT-KO mice [143]. However, MT-KO mice showed a reduced level of phosphorylated synapsin in the frontal cortex along with decreased expressions of spinophilin in the frontal cortex and hippocampus, suggesting a decrease in synaptic activity [143].

In cultured rat hippocampal neurons, melatonin was confirmed to enhance GABAergic inhibitory transmission by the whole-cell patch-clamp technique. This voltage-independent enhancement did not change the ion selectivity of the GABA_A receptors and it was not blocked by luzindole, which is a melatonin receptor antagonist, suggesting an allosteric modulation of melatonin by binding to the sites of GABA_A receptors [152]. Melatonin was found to increase the number of GABA binding sites to benzodiazepine receptors in rat hippocampal slices [153]. It enhances GABA concentrations and affinity of its receptors, also increases the inhibitory transmissions via GABAergic synapses in the brain [154]. In vivo experiments demonstrated that, melatonin administration increases GABA accumulation in several brain regions including hypothalamus, cerebellum, cerebral cortex and pineal gland [155]. Melatonin increased GABA_C-receptor activity, as verified by the ability of the GABA_C-receptor antagonists, picrotoxin and TPMPA, to abolish the effects of melatonin [156]. In addition, several studies indicated that melatonin exerts an enhancing influence on GABAergic activity by increasing GABA binding, turnover, and GABA-induced chloride ion uptake [157 –159]. These observations raised the possibility that melatonin might also influence the other two GABA receptors, the ionotropic GABA_A [160] and the metabotropic GABA_B receptors [161]. A loss of hippocampal GABAergic inhibition is believed to underlie the neuronal hyperexcitability. The ability of melatonin to increase GABA level is regarded as a possible mechanism of melatonin-mediated neuroprotection [152, 162].

The regulation of melatonin on the calcium-dependent DA release was shown in the early 1980s [163, 164]. In aged rats, melatonin and its precursor L-tryptophan exerted a long-term effect on the 5-hydroxytryptamin (5-HT), DA and norepinephrine (NE) neurotransmission by enhancing monoamine synthesis [165]. Studies in Parkinson’s disease models showed melatonin not only prevented the decrease of DA but also rescued the loss of dopaminergic neurons [166, 167]. Melatonin mediated the inhibition of DA release is evident in specific areas, including the hypothalamus, hippocampus and retina [168], among which the interaction between melatonin and DA in the anterior hypothalamus has been mostly noted. Indeed, both acute and chronic melatonin administrations protect dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [169], rotenone [170], and 6-hydroxydopamine (6-OHDA) [171]. Effects of melatonin are also associated with a reduction in striatal dopaminergic activity via the dopamine D1 and D2 receptors, which in turn inhibits glutamate release [172].

A circadian rhythm of DA, glutamate and GABA was found in both the striatum and nucleus accumbens in rats [173]. By in vivo microdialysis, the day: night variations in glutamate and GABA were suggested to be related to the daily changes in endogenous melatonin production [174]. And the number of the GABA_A receptors fluctuated with a maximum at night [175]. During the dark cycle there was a significant increase in the concentration of DA compared with the light cycle [176]. Additionally, circadian changes in astrocytes have been reported, suggesting an activation of glia cells occurs during the light [177]. The rhythmic release of neurotransmitters and the rhythmic activation of different cells in brain involving melatonin are still poorly understood.

PINEAL DYSFUNCTION, CIRCADIAN DISRUPTION, AND INFLAMMATION IN MELATONIN DECLINE OF AD

The aging related decline of melatonin is thought to be a result of the pineal calcification, which increases with aging [178 –180]. Thus, pineal calcification increases the risk for AD [181]. Although some age-related molecular and histochemical changes in the pineal gland have recently been described in AD patients, the mechanisms behind the deteriorations of circadian rhythms and melatonin production have not yet been fully elucidated. Disruptions of normal circadian rhythms and sleep cycles are consequences of aging [182]. The fragmented sleep-wake pattern is even more pronounced in AD patients [183, 184]. Sleep deficit or fragmented sleep in normal populations is a risk factor for the future development of AD [185, 186]. Many AD patients often suffer from circadian system related behavioral disturbances, such as daytime agitation and nightly restlessness [19, 187]. A higher level of irregularities in melatonin secretion have been observed in AD patients with disturbed circadian rhythms [188]. Besides AD, circadian disruption and the reduced level of melatonin have been reported to increase the risk for other brain diseases such as stroke, Parkinson’s disease, epilepsy, insomnia and neuropsychiatric disorders [189]. Intracranial calcification occurs both in physiological and pathological conditions. Although the structural and histochemical characteristics of pineal calcifications have been described in detail, their biogenesis remains unknown [190]. It was reported that the calcification results from the death or degeneration of the pinealocytes, which leads to the decreased pineal activity [191, 192]. In addition, the number of light pinealocytes decreases with aging [18]. Aging leads to an increase in the number of dark pinealocytes, which are characterized by intra-nuclear deposits of calcium and many other signs of degeneration [193]. In AD patients, the amount of uncalcified pineal tissues was markedly less than that in patients with other dementia such as depression, or in healthy controls [181]. Since uncalcified pineal size is associated with melatonin excretion [194], the reduction of melatonin would generate a further increase of oxidative damage and lead to an increased Aβ deposition. Some studies suggested that the reduced level of melatonin is not only associated with AD, but also may play an important role in its pathogenesis [181]. Accordingly, pineal dysfunction and reduced melatonin levels may be an early marker of AD [20].

Inflammation may influence the melatonin secretion [195]. It is now accepted that the immune privilege of the brain is not absolute, and the cells in brain are sensitive to both the inflammatory events occurring in the periphery and the infiltration of peripheral immune cells [196]. The pineal gland is a part of the brain that lacks the blood-brain barrier, which allows the immune mediators have easy access into it. The secretory activity of the pineal gland may be affected by immune mediators present in the CSF because during peripheral inflammation, the pro-inflammatory cytokines, including interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF α) can cross the blood-brain and blood-CSF barriers and reach the brain parenchyma [197 –199]. IL-1β was reported to suppress nocturnal melatonin secretion in sheep regardless of the photoperiod, which may be resulted from the decreased synthesis of the melatonin intermediate serotonin [200], and inhibit the expressions of the melatonin rhythm enzyme AANAT and HIOMT [200]. A study on denervated pineal glands in rats showed that TNFα inhibited the transcription of AANAT and the synthesis of the melatonin precursor N-acetylserotonin [201]. Moreover, melatonin synthesis may be affected by the autocrine actions of inflammatory mediators, as reported that, in addition to producing melatonin, the pineal gland can be induced to synthesize several cytokines, such as IL-1β, IL-6, and TNF [202 –205]. Inflammation is also involved in the AD progression.AD patients are more vulnerable to peripheral infection than their age-matched healthy controls as the innate immune systems undergo changes with aging or in AD [206]. In a recent study, Aβ directly impairs melatonin synthesis and melatonin receptor signaling at the pineal gland [207]. In the pineal glands of rats, Aβ treatment elicited an inflammatory response, evidenced by the up-regulation of 52 inflammatory genes, and decreased the production of melatonin up to 75% compared to vehicle-treated glands [207]. Additionally, light is able to either suppress or synchronize melatonin production according to the light schedule [208].

SYNAPTIC PROTECTIONS OF MELATONIN

Clinically, melatonin supplement is benefit improving cognitive impairment of AD. Prophylactic melatonin significantly reduced AD neuropathology and its associated cognitive deficits in a manner that is independent of antioxidant pathways in a mouse model of AD [209]. Melatonin stabilized the cognitive function in AD patients over a 2-3 year period [210] and improved cognitive performances in individuals with mild cognitive impairment [211]. A 3-year course of melatonin treatment to one of a pair of monozygotic AD twins resulted in milder cognitive impairment for the treated twin [212]. The effects of add-on prolonged-release melatonin (2 mg) to standard therapy on cognitive functioning and sleep were investigated in 80 patients diagnosed with mild to moderate AD. Add-on prolonged-release melatonin has positive effects on cognitive functioning and sleep maintenance in AD patients compared with placebo, particularly in those with insomnia comorbidity [29].

In OXYS rats (an established model of sporadic AD), melatonin significantly increased hippocampal synaptic density and the number of excitatory synapses [213]. Melatonin has been demonstrated to directly interact with Aβ to prevent its aggregation and inhibit the progressive formation of β sheet and/or amyloid fibrils [214, 215]. Thus, melatonin could protect Aβ-induced impairments of neuronal cooperative activity, hippocampal synaptic plasticity and LTP [128]. Melatonin improved dendritic arborizations by upregulating the growth-associated protein-43 (GAP-43) and PSD-95 proteins in cultured neurons exposed to glutamate [216]. Compared with controls, melatonin treated rats subjected to transient focal cerebral ischemia had significant improvement in GAP43, PSD95 and matrix metalloproteinase 9 (MMP9) in the brain [216]. MMPs have central roles in the development and maturation of dendritic spines [217] which are required for the maintenance of LTP [218, 219]. All these studies suggested that the administration of melatonin may protect and improve LTP under pathological conditions including AD.

The specificity of the effect of melatonin treatment on memory consolidation was confirmed using MT1/MT2 receptor antagonists prior to melatonin treatment [220]. Ramelteon is the first melatonin receptor agonist approved by the U.S. Food and Drug Administration to be used in the treatment of insomnia [221], which not only has the potential in improving the sleep quality of AD but also can offer neuroprotection in AD [222]. Piromelatine (Neu-P11), a novel agonist for MT1 and MT2 receptors and a serotonin 5-HT1A/1D receptor, improved the neuronal and cognitive impairment induced by intrahippocampal Aβ_1 - 42 injection in a rat model of AD [223].

As MT2 receptor is involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, AD and pain, and the selective MT2 receptor agonists show hypnotic and anxiolytic properties, MT2 receptor has a great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available [224].

CONCLUSION

Melatonin plays important roles in synaptic stability and synaptic plasticity, and further benefit to cognition. Although MT1 is a part of the presynaptic protein network, we still do not understand how melatonin exerts different actions on LTP in physiological and pathological conditions, which might involve cell type specific or synapse specific distributions of melatonin receptors. Melatonin declines in the very early stage of AD, and its two important receptors, MT1 and MT2, are shown deficit in AD brain. More studies are needed to reveal the region specific or cell type specific alterations of melatonin receptors in the early stage of AD, which could contribute to find more effective targets for synaptic protection of AD.

Considerable studies support that melatonin exerts the effect on anti-Aβ aggregation and protects against Aβ-induced neurotoxicity in vitro and in vivo [225]. And melatonin has often been reported to prevent or decrease tau hyperphosphorylation [225], have anti-inflammatory (and occasionally pro-inflammatory) properties in many species, including humans [226], and act as an antioxidant [227]. Another mechanism through which melatonin may protect against cognitive impairments of AD is through stabilizing the structures of synapses and enhancing the functions of synapses as reviewed in this paper. Thus, melatonin appears to exert multiple complementary mechanisms of action in the brain and may be a promising therapeutic against AD.

Footnotes

ACKNOWLEDGMENTS

This work was supported in parts by grants from the National Natural Science Foundation of China (91539112, 31721002). We gratefully thank Dr. Xin-an Liu from Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai for her careful revisions of this paper.

Authors’ disclosures available online ().

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