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Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan
metabolite, is synthesized mainly by the pineal gland.
Melatonin has a number of physiological functions, including
regulating circadian rhythms, clearing free radicals,
improving immunity, and generally inhibiting the oxidation of
biomolecules. It is generally accepted that melatonin deficit
is closely related to aging and age-related
diseases[1]. Decreased levels of melatonin in serum and in cerebrospinal
fluid (CSF) and the loss of melatonin diurnal rhythm are
observed in patients with Alzheimer disease
(AD)[2-6]. Interestingly, the level of melatonin in CSF decreases with
the progression of AD neuropathology as determined by
the Braak stages[6]. 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[2,6]. A strong correlation exists between pineal content and CSF level of
melatonin[2] 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. Although the
pineal gland of AD patients has molecular changes, no
changes in pineal weight, calcification or total protein
content have been observed[2,8]. A recent study showed that
b1-adrenergic receptor mRNA disappeared, and MAOA activity and gene expression 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[2]. In AD patients, 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[9-13]. Therefore, melatonin supplementation may be one of the possible strategies
for symptomatic treatment. Moreover, melatonin treatment
seems to be safe because of its marked low
toxicity[14,15]. However, adverse drug reactions may occur, such as (i)
fever on the first day of melatonin treatment, which is possibly
a reaction to the thermoregulatory function of melatonin; (ii)
hyperkinesia or complaints of restless legs; (iii) menorrhagia,
which may be explained by a decrease in plasma
follicle-stimulating hormone (FSH) and luteinizing hormone (LH);
(iv) pigmentation on arms and legs; (v) headache and
abdominal reactions, such as nausea, dyspepsia and
abdominal pain; (vi) thrombosis; and (vii)
drowsiness[16,17]. When a pharmacological dose of melatonin (3.0 mg) is administered
to elderly people, it not only induces sleep but also induces
hypothermia. Moreover, intravenous administration of me latonin to schizophrenic patients in remission causes a
worsening of psychotic symptoms, which persists even after the
treatment is interrupted[18]. Pregnant women should avoid
melatonin, because its (functional) teratological effects are
not known. Additionally, there are also concerns with
regard to the potential vasoactive nature of melatonin.
There are two characteristic pathologies in the brains of
patients with AD: neurofibrillary tangles (NFT) composed of
hyperphosphorylated microtubule-associated protein tau,
and senile plaques (SP) mainly composed of Ab peptide,
derivations from the proteolytic processing of amyloid
precursor protein (APP)[19]. Convincing evidence indicates that
Ab can mediate neurotoxicity through a complex series of
interactions that involves increasing free radicals, raising
intracellular calcium concentrations, and even triggering
apoptosis[20]. Ab is generally believed to play a major 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[21]. Tau protein is a major microtubule-associated protein that promotes
microtubule assembly and stabilizes microtubules; it also
takes part in the formation and maintenance of the axonal
structure[22]. Hyperphosphorylated tau reduces the ability
to stabilize microtubules, leading to disruption of the
cytoskeletal arrangement and neuronal
transport[23,24]. The extent of neurofibrillary pathology, and particularly the
number of cortical NFT, correlates positively with the severity of
dementia[25]. Although the exact pathogenesis of AD is not
fully understood, both Ab deposition and tau
hyperphos-phorylation play critical roles in the development of AD.
Because melatonin is able to improve some of the clinical
symptoms of AD, and because melatonin levels decrease
dramatically during AD, studies on the relationship between
melatonin and tau/Ab pathology will be helpful to
understand and to assess its potential in the prevention or
treatment of AD. This review will address the protective
effects of melatonin on the pathological development of AD. Most
of the data presented here are from animal studies, because
the efficacy of melatonin in preclinical AD is currently not
well documented.
Role of melatonin in tau hyperphosphorylation
Effect of melatonin on cytoskeletal reorganization
The cytoskeleton plays a key role in maintaining the highly
asymmetrical shape and structural polarity of neurons that are
essential for neuronal physiology, and cytoskeletal
reorganization plays a key role in neurogenesis. In
neurodegenera-tive diseases, the cytoskeleton is abnormally
assembled, and
impairment of neurotransmission
occurs[26,27]. Current data indicate that melatonin promotes neurogenesis through
cytoskeletal rearrangements in a receptor-dependent and
possibly subtype-selective
manner[24,25]. Melatonin receptor 1 (MT1) is thought to be responsible for melatonin-induced neurite formation[28,29]. In addition, to promote microtubule rearrangement through Ca2+/calmodulin
antagonism[30], melatonin could modulate phosphorylation and
organization of vimentin intermediate filaments via protein
kinase C activation in N1E-115
cells[31,32]. Alterations in cyto-skeletal organization and melatonin levels in aging and
neurodegenerative diseases support the notion that
cyto-skeletal disruption is presumably associated with melatonin
deficiency. These observations prompted us to investigate
whether melatonin has beneficial effects on tau
hyperphos-phorylation, one of the characteristic pathological features
in the AD brain.
Inhibition of tau hyperphosphorylation by melatonin
Cytoskeletal alterations in AD are predominantly
characterized by intracellular NFT mainly composed of an abnormal
hyperphosphorylated form of the microtubule-associated
protein, tau[33]. In healthy neurons, tau binds and stabilizes
microtubules, which make up the cytoskeleton of the cell, by
a reversible enzymatically mediated phosphorylation and
dephosphorylation process. Hyperphosphorylation of tau
leads to a decreased affinity with microtubules and the
disruption of the neuronal cytoskeleton, as well as resulting in
resistance to proteolytic degradation and gradual
accumulation in the cell body[34].
The phosphorylation of tau is strictly regulated by a panel
of protein phosphatases and protein
kinases[35]. Inhibition of tau hyperphosphorylation is one target in AD treatment.
Recently, we systemically studied the effect of melatonin on
tau hyperphosphorylation induced by a series of activators
of protein kinases and inhibitors of protein phosphatases.
We found that melatonin efficiently attenuates tau or
neurofilament hyperphosphorylation induced by
wortmannin[36], calyculin
A[37,38] and okadaic
acid[39] in N2a and SH-SY5Y neuroblastoma cells. Our
in vivo studies further demonstrated that melatonin significantly ameliorated tau
hyper-phosphorylation elicited by wortmannin[40]
and isoprotere-nol[41,42] in rats. To elucidate the mechanisms underlying the
inhibitory effect of melatonin on tau hyperphos-phorylation,
alterations of the activities of protein kinases and
phosphatases were detected. Melatonin treatment not only
inhibited wortmannin-induced glycogen synthase kinase-3
(GSK-3) activation, isoproterenol-induced protein kinase A
(PKA) activation, and calyculin A-induced protein
phosphatase-2A (PP-2A) inactivation, but also antagonized the oxidative stress induced by these agents
[34,35,40]. These results from our studies provide supportive evidence for the strong
efficacy of melatonin supplementation in inhibiting tau
hyperphosphorylation induced by other stimuli. The next
question is whether a decrease in melatonin levels would
alter the phosphorylation state of the tau protein. To answer
this question, we inhibited melatonin biosynthesis by
injecting haloperidol, an inhibitor of
5-hydroxyindole-O-methyltransferase (one of the key enzymes in melatonin
synthesis), into the lateral ventricle and the peritoneal
cavity in rats[43]. The decreased serum level of melatonin, as
detected by fluorescence high-performance liquid
chromato-graphy, confirmed the successful inhibition of melatonin
biosynthesis by haloperidol. More importantly, we found that
inhibition of melatonin biosynthesis not only resulted in
spatial memory impairment in rats, but also induced a
reduction in tau phosphorylation with a concomitant decrease in
PP-2A activity. Supplementation with melatonin by prior
injection for 1 week and reinforcement during the
haloperidol administration period significantly improved memory
retention deficits, arrested tau hyperphosphory-lation and
oxidative stress, and restored PP-2A
activity[43]. As far as we know, this is the first report providing direct evidence for the
physiological regulation by melatonin of tau phosphorylation,
and PP-2A activity, as well as spatial memory. This finding
is of great interest and significance because of the profoundly
decreased melatonin levels and reduction in PP-2A activity
in AD brain[44]. Although it is unclear whether diminished
melatonin concentration is one of the causative factors or
only a secondary process in AD pathology is unclear, our
results strongly implicate decreased melatonin in
Alzheimer-like spatial memory impairment and tau
hyperphosphoryla-tion, as well as reduced PP-2A activity. Melatonin may play
an important role in maintaining the physiological activity of
PP-2A through a currently unknown mechanism, and
decreased melatonin may be critical in the development of
neurofibrillary degeneration. As haloperidol not only inhibits
5-hydroxyindole-O-methyltransferase, but also antagonizes
dopamine D2 receptors, it is important to explore more
selective means to suppress melatonin levels in the brains of experimental animals.
Possible mechanisms underlying the effect of
melatonin on tau hyperphosphorylation
Chemical agents used in
our studies, including wortmannin, isoproterenol and
calyculin A, not only induced tau phosphorylation, but also
initiated oxidative stress, as manifested by an elevated level
of malondialdehyde and an altered activity of superoxide
dismutase[36,37,39]. Furthermore, melatonin is a potent direct
free radical scavenger and indirect antioxidant that acts by
augmenting the activity of several important antioxidative
enzymes, for example superoxide dismutase, glutathione
peroxidase and glutathione reductase[45]. Oxidative stress is known to influence the phosphorylation state of
tau[46-48]. In a more recent study we have also demonstrated that calyculin
A, a selective inhibitor of protein phosphatase of PP-2A and
PP-1 that has little or no direct effect on other phosphatases
or kinases, induced a significant activation of GSK-3 via
oxidative stress[35]. It is therefore possible that prevention
against tau phosphorylation by melatonin is partially due to
antioxidant activity.
However, more importantly, although the precise
underlying mechanisms are not fully understood, melatonin may
act as an enzyme modulator in a way that is unrelated to its
antioxidant properties. Accumulating data provide evidence
for the regulation by melatonin of protein kinases including
PKA[49,50], protein kinase C
(PKC)[29,51], Ca2+/calmodulin-dependent kinase II(CaMKII)[52], and the mitogen-activated
protein kinase (MAPK) family[53]. The documented
correlation between melatonin and cAMP indicates that melatonin
might inhibit PKA activity through the melatonin
receptor-coupled inhibition of adenylyl cyclase and reduction of
cAMP[49,50]. Although there is no evidence of a direct
relationship between melatonin and GSK-3 activity, a recent
study has found that melatonin treatment leads to elevated
phosphorylation of Akt[54], an upstream regulator of GSK-3.
It is possible that melatonin might at least partially inhibit
GSK-3 activity through activating the phosphatidyl
inositol-3 kinase (PI-3K)/Akt signaling pathway. Considering the
regulation of GSK-3 activity by other protein kinases, we
cannot exclude the possible contribution of
melatonin-induced activation of the PKC and MAPK families. Based on
our own studies and those by other groups, we believe that
melatonin may function as an upstream modulator of
extensive protein kinases and protein phosphatases, and GSK-3
is one of the most implicated as targets (Figure 1). Further
study is necessary to fully elucidate the signal transduction
modulated by melatonin.
Melatonin and Ab toxicity
Regulation by melatonin of A b generation
Ab is composed of 39-43 amino acid residues derived from proteolytic
processing of a large precursor, APP, and plays a pivotal
role in the dysfunction and death of neurons in
AD[19,21]. Mature APP is processed proteolytically by distinct a-secretase or b-secretase pathways[55].
The nonamyloido-genic a-pathway involves the cleavage of APP within
the Ab sequence by a-secretase to release an N-terminal APP fragment, which in turn is cleaved by g-secretase. Thus, the
cleavage by g-secretase precludes the formation of
Ab. The amyloidogenic b-secretase pathway, which results in the
formation of intact Ab peptide, is mediated by the sequential
cleavage of b-secretase and g-secretases at the N- and
C-terminals of the Ab sequence,
respectively[64].
Melatonin has been found to have regulatory effects on
APP metabolism. Melatonin treatment inhibited normal
levels of secretion of soluble APP (sAPP) in different cell lines
by interfering with APP full
maturation[56]. Melatonin also affected the mRNA level of APP in a cell type-specific manner.
Pretreatment with melatonin resulted in a significant
reduction in the APP mRNA level in PC12 cells, but
failed to produce this effect in human neuroblastoma
cells[57]. We have also demonstrated that melatonin reduces
Ab generation in mouse neuroblastoma N2a cells harboring
APP695[58]. An in
vivo study showed that melatonin did not affect the expression
of APP holoprotein in transgenic Tg2576
mice[59]. Addi-tionally, administration of melatonin efficiently reduced
Ab generation and deposition in
vivo[59,60] and in
vitro[56-58,61]. However, a recent study showed that, despite achieving high
plasma concentrations of melatonin, chronic melatonin
therapy in old Tg2576 mice initiated at 14 months of age not
only failed to remove existing plaques, but also failed to
prevent additional Ab deposition. This result is in contrast
with those of diminished Ab in melatonin-treated wild type
mice[60] and reduced Ab and protein
nitration in melatonin-treated Tg2576
mice[59]. The age at initiation of melatonin
treatment may be the key difference that accounts for the
discrepancy between the studies of Matsubara et
al[59] and Quinn et
al[62], in which the same transgenic Tg2576 mouse
model was used. Amyloid plaque pathology typically
appears in Tg2576 mice at 10-12 months of
age[63]. Melatonin treatment in the study of Matsubara
et al was started at 4 months of age (prior to the appearance of hippocampal and
cortical plaques)[59], an earlier pathological stage compared
with 14 months of age in the study of Quinn et
al[62]. However, both studies concur in finding little evidence of the potent
antioxidant effects of melatonin in the oldest mice. These
findings indicate that melatonin has the ability to regulate
APP metabolism and prevent Ab pathology, but fails to exert
anti-amyloid or antioxidant effects when initiated after the
age of Ab deposition.
Although consistent conclusions were achieved, none
of the related studies further explain how melatonin exerts its
inhibitory effect on Ab generation. The proteolytic cleavage
of APP by the a-secretase pathway is regulated by many
physiological and pathological stimuli; the PKC-dependent
mechanism is one of the most recognized. Stimuli such as
muscarinic and metabotrophic glutamate receptor agonists
and phorbol esters share the capacity to stimulate soluble
APP secretion and inhibit Ab formation through PKC
activation[64]. The mechanism whereby PKC activity increases
soluble APP secretion is still unknown, but it may involve
additional kinase steps and the eventual activation of the
secretases that mediated APP cleavage. Recently, the
inhibitory regulation by GSK-3 on Ab generation has been
well established[65-67]. GSK-3 interacts with presenilin-1,
a cofactor for g-secretase, implying that GSK-3 may function as
a component in the g-secretase
complex[68,69]. Assuming that melatonin can influence PKC and GSK-3 activity as
mentioned earlier, it is postulated that melatonin may regulate
APP processing through the PKC and GSK-3 pathways.
Because PKC is an upstream regulator of GSK-3, GSK-3 may
be one of the common signal pathways that regulate both
Ab generation and tau hyperphosphorylation (Figure 1).
Regulation by melatonin of the formation of
Ab fibrils
Important pathological properties of
Ab, such as neurotoxicity and resistance to proteolytic degradation, depend on the
ability of peptides to form b-sheet structures and/or amyloid
fibrils[70,71]. Intervention in the Ab aggregation process can
be considered an approach to stopping or slowing the
progression of AD. Melatonin can interact with
Ab40 and Ab42 and inhibit the progressive formation of
b-sheet and/or amyloid fibrils[72-74]. The antifibrillogenic effect of melatonin has
been demonstrated by different techniques, including
circular dichroism (CD) spectroscopy, electron microscopy and
nuclear magnetic resonance (NMR) spectroscopy, and
electrospray ionization mass spectrometry
(ESI-MS)[73]. Moreover, the interaction between melatonin and
Ab appears to depend on the structural characteristics of
melatonin rather than on its antioxidant properties, because it could
not be reproduced by melatonin analogs or other free radical
scavengers[70,72]. Evidence derived from ESI-MS proved that
there was a hydrophobic interaction between Ab and
melatonin, and proteolytic investigations suggested that the
interaction took place on the 29-40 residues of the
Ab segment[73]. Results from NMR spectroscopy further confirmed
a residue-specific interaction between melatonin and any of
the three histidine and aspartate residues of
Ab[74]. The imidazole-carboxylate salt bridges formed by the side chains of
histidine (His+) and aspartate
(Asp-) residues are critical to the formation of the amyloid
b-sheet structures[75], and disruption of these salt bridges promotes fibril
dissolution[76]. Melatonin could promote the conversion of
b-sheets into random coils by disrupting the imidazole-carboxylate salt
bridges and thus prevent Ab fibrillogenesis and aggregation.
It is therefore possible that by blocking the formation of the
secondary b-sheet conformation, melatonin may not only
reduce neurotoxicity but also facilitate clearance of the
peptide via increased proteolytic degradation.
Protective effects of melatonin on Ab-induced toxicity
It has been postulated that Ab, a major component of SP, is
responsible for the neuronal degeneration observed in the
vicinity of SP in the AD brain, and is responsible for the
disease pathology. Ab treatment elicits a spectrum of
cellular damage, including increases in lipid peroxidation and
intracellular free calcium concentration, oxidative damage to
mitochondrial DNA, and the emergence of apoptotic
markers[18]. Oxidative stress acts synergistically with disturbance
of intracellular calcium homeostasis: the free radical-induced
membrane damage induces further calcium influx, and the
resultant accentuated calcium influx in turn will induce the
generation of further free radicals. Therefore, oxidative stress
plays a central role in Ab-induced neurotoxicity, and even
cell death. Aside from Ab causing oxidative stress, it has
been proposed that oxidative damage could exacerbate a
vicious cycle, in which amyloidogenic processing of APP
would be further facilitated to generate more Ab, which in
turn enhances oxidative stress[77]. Accumulating data
implies that melatonin efficiently protects cells against
Ab-induced oxidative damage and cell death in
vitro[78,79] and in
vivo [59,80-82]. In Ab-treated cells and animals, melatonin
exerts its protective activity mainly through an antioxidant
effect, whereas in APP-transfected cells and
transgenic animal models, the underlying mechanism is attributed to not
only its antioxidant property, but also its anti-amyloid
property, including inhibition of both Ab generation and
formation of b-sheets and/or amyloid fibrils. However, it is difficult to
determine the extent of the contribution from each of these
properties to the overall effects of melatonin treatment
in vivo.
Other neuroprotective effects of melatonin
Protection of the cholinergic system In cholinergic
neurons, the synthesis of ACh by choline acetyltransferase
(ChAT) is dependent on intracellular pools of choline
provided by high-affinity choline uptake and of acetyl-CoA
replenished by metabolism. In a subsequent step, newly
synthesized ACh is transported into synaptic vesicles by the
energy-dependent vesicular ACh transporter. Biological
investigations of tissue from biopsy and autopsy have found
a profound decrease in the activity of the ACh-synthesis
enzyme, ChAT, in the neocortex, which correlates positively
with the severity of dementia[83]. Reduced choline uptake,
ACh release and loss of cholinergic neurons from the basal
forebrain region further indicate a selective presynaptic
cholinergic deficit in the hippocampus and neocortex of individuals with AD. The degeneration of the cholinergic
innervation from the basal forebrain to the hippocampal
formation in the temporal lobe is thought to be one of the factors
determining the progression of memory decay both during
normal aging and AD. The mechanism of reduced
cholinergic function remains unclear, but it is thought that
Ab has negative effects on multiple aspects of ACh synthesis and
release, including choline uptake, ChAT activity and ACh
release[83]. A previous study has also demonstrated that
melatonin partially prevented peroxynitrite-induced
inhibition of choline transport and ChAT
activity[84]. Recently, Feng et
al reported that 8-month-old APP695 transgenic mice
had not only Ab deposition but also significant learning and
memory deficits, as well as cholinergic system dysfunction,
as indicated by a profound reduction in ChAT activity in the
frontal cortex and hippocampus. Long-term melatonin
treatment (4 months) significantly ameliorated such
neuropatho-logical, behavioral and biochemical changes in
APP695 transgenic mice[80]. Another study by Feng
by et al also showed that similar treatment with melatonin antagonized
spatial memory impairment and decreased ChAT activity in
ovariectomized adult rats[85]. Additionally, an inhibitory
effect of melatonin on ACh release was found in intact rabbit
retinas[86]. These findings indicate that protection of the
cholinergic system may occur at multiple steps that are
critical for ACh synthesis and release (Figure 2).
Anti-inflammatory actions
Epidemiological studies have
shown that non-steroidal anti-inflammatory drug (NSAID)
use decreases the incidence of AD[87].
Ab itself has been shown to act as a proinflammatory agent that causes the
activation of many inflammatory components, and SP
co-exist with cytokines and chemokines, and are surrounded by
microglia and astrocytes, indicating the involvement of
inflammation in the pathogenesis of
AD[88]. The activated microglia induced by
Ab are the major sources of inflammatory response. Microglial activation might involve beta-amyloid
binding and the activation of cell surface immune and
adhesion molecules[89]. It has been reported that melatonin
attenuates kainic acid-induced microglial and astroglial
responses as determined by immunohistochemical detection
of isolectin-B4 and glial fibrillary acidic protein (GFAP), the
specific markers for microglia and astroglia,
respectively[90]. Oral melatonin administration also attenuated
Ab-induced proinflammatory cytokines in rat
brain[82]. A recent study showed the potent suppressive effect of melatonin
pretreatment on the ischemia-reperfusion-stimulated ipsilateral
increase in the immunoreactivity for neuronal NO synthase
(nNOS), cyclooxyrenase-2 (COX-2) or myeloperoxidase
(MPO), but not for GFAP, suggesting the contribution of anti-inflammatory response in neuroprotection against
ischemia-reperfusion damage[91]. Nuclear factor-kappaB
(NF-kB) plays an important role in inflammatory
mediator-mediated signal transduction. Melatonin has been shown to
inhibit tumor necrosis factor (TNF) and brain injury-induced
NF-kB activation[92,93]. These results suggest that the
anti-inflammatory properties of melatonin are due to inhibition of
the production of inflammatory mediators and downstream
signal transduction.
Expectations
Melatonin has been proposed as a treatment for AD
based on the fact that the level of melatonin reduces during
aging and in AD patients, as well as for its antioxidant and
anti-amyloid effects. Recent studies from APP transgenic
mice have indicated that early, long-term melatonin
supplementation produces anti-amyloid and antioxidant effects, but
no such effect is produced when melatonin treatment is
initiated after the age of amyloid
formation[58-61]. Extensive clinical trials and studies with transgenic models are
necessary to confirm the role of melatonin at the late pathological
stage of AD. If melatonin has no effect at the late stage of
AD, studies on melatonin should be limited to the
prevention of AD, rather than treatment. Our studies have
demonstrated the efficacy of melatonin in the inhibition of tau
hyperphos-phorylation. As mentioned earlier, GSK-3 may
be one of the common signaling pathways that
regulates both Ab generation and tau phosphorylation. Moreover,
GSK-3 is considered to be a key protein kinase involved in
Ab-induced tau hyperphosphorylation. Therefore, the
regulation by melatonin of protein kinases, especially GSK-3, is
worthy of further exploration. Although GSK-3 has been
implicated as a central player in the altered metabolism of
both tau and Ab, mechanistic links between melatonin and
GSK-3 have so far been only indirectly evidenced by the
sole fact that phosphorylation of a GSK-3 regulator, Akt, in
the brain is augmented by treatment with melatonin. Future
research strategies will need to overcome the current
limitations on insights into the direct functional coupling between
melatonin and GSK-3. For instance, experimental paradigms
such as the one provided by a recent study using a mouse
model of tauopathy[94] could be applied to examination of the
hypothesis of melatonin- and GSK-3-mediated
neurodegen-erative tau pathogenesis. In mammals melatonin exerts some
of its functions through two specific high-affinity membrane
receptors belonging to the superfamily of G-protein-coupled
receptors: MT1 and MT2. Decreased MT2 immunore
activity and increased MT1 immunoreactivity have been
reported in the hippocampus of AD
patients[95,96]. The connection between changes in receptor expression and the
unsatisfactory therapeutic effects of melatonin when started at
a late pathological stage of AD remain to be elucidated.
As a conclusion, in addition to its well-established
antioxidant effect, melatonin prevents cells from
Ab-mediated toxicity not only by inhibiting Ab generation but also by
inhibiting Ab aggregation and formation of amyloid fibrils.
Furthermore, melatonin attenuates tau hyperphosphorylation
induced by activation of protein kinases or inhibition of
protein phosphatases. Moreover, melatonin may be involved
in the physilogical regulation of tau phosphorylation. Early,
long-term application of melatonin may at least slow down
the development of AD.
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