Molecular Neurobiology

, Volume 56, Issue 12, pp 8255–8276 | Cite as

Melatonin in Alzheimer’s Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer’s Neuropathology

  • Md. Farhad Hossain
  • Md. Sahab UddinEmail author
  • G. M. Sala Uddin
  • Dewan Md. Sumsuzzman
  • Md. Siddiqul Islam
  • George E. Barreto
  • Bijo Mathew
  • Ghulam Md AshrafEmail author


Melatonin, a pineal gland synthesized neurohormone is known as a multifunctioning pleiotropic agent which has a wide range of neuroprotective role in manifold age-related neurodegenerative disorders especially Alzheimer’s diseases (AD). AD is a devastating neurodegenerative disorder and common form of dementia which is defined by abnormal and excessive accumulation of several toxic peptides including amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). The Alzheimer’s dementia relates to atrophic changes in the brain resulting in loss of memory, cognitive dysfunction, and impairments of the synapses. Aging, circadian disruption, Aβ accumulation, and tau hyperphosphorylation are the utmost risk factor regarding AD pathology. To date, there is no exact treatment against AD progression. In this regard, melatonin plays a crucial role for the inhibition of circadian disruption by controlling clock genes and also attenuates Aβ accumulation and tau hyperphosphorylation by regulating glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinase-5 (CDK5) signaling pathway. In this review, we highlight the possible mechanism of AD etiology and how melatonin influences neurogenesis by attenuating circadian disruption, Aβ formation, as well as tau hyperphosphorylation. Furthermore, we also find out and summarize the neuroprotective roles of melatonin by the blockage of Aβ production, Aβ oligomerization and fibrillation, tau hyperphosphorylation, synaptic dysfunction, oxidative stress, and neuronal death during AD progression.


Melatonin Alzheimer’s disease Amyloid β Neurofibrillary tangles Circadian rhythm 



Alzheimer’s disease

amyloid β


amyloid protein precursor


N-acetylserotonin by arylalkylamine N-acetyltransferase


arginine vasopressin






advanced glycation end products


a disintegrin and metalloproteinase domain-containing protein-10


aromatic amino acid decarboxylase


brain muscle ARNT-like 1


cerebrospinal fluid




circadian locomotor output cycles kaput




choline acetyltransferase


complement 1q


copper-zinc superoxide dismutase


cyclin-dependent kinase 5


endoplasmic reticulum


glutathione peroxidase


hydrogen peroxide








kainic acid




long-term potentiation


long-term depression


mild cognitive impairment


manganese superoxide dismutase


neurofibrillary tangles


nitric oxide


nitric oxide synthase 2


nuclear factor kappa beta


phospholipase C


protein kinase C


phosphatidylinositol 3-kinase


period circadian protein homologue






reactive oxygen species


retinohypothalamic tract


superoxide dismutase


suprachiasmatic nucleus


superior cervical ganglion


sirtuin 1


tumor necrosis factor-α


vasoactive intestinal peptide




B cell lymphoma 2


protein phosphatase 2A


glycogen synthase kinase 3 beta


protein kinase-A


BCL2 associated X


prostate apoptosis response-4


c-JUN N-terminal kinase


extracellular signal-regulated kinase


monoamine oxidase A


receptor for advanced glycation end products


glial fibrillary acidic protein


ionized calcium binding adaptor molecule 1


apolipoprotein E


poly(ADP-ribose) polymerase-1



The authors are grateful to the Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.

Author Contributions

This work was carried out in collaboration between all authors. MSU and GMA conceived the original idea and designed the outlines of the study. MFH, MSU, GMSU, and DMS wrote the draft of the manuscript. MSU prepared the figures of the manuscript. GEB, MSI, and BM reviewed the scientific contents of the manuscript. All authors read and approved the final submitted version of the manuscript.


The author(s) received no financial support for the research, authorship, and publication of this manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Shukla M, Govitrapong P, Boontem P et al (2017) Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr Neuropharmacol 15:1010–1031. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Uddin MS, Al Mamun A, Asaduzzaman M et al (2018) Spectrum of disease and prescription pattern for outpatients with neurological disorders: an empirical pilot study in Bangladesh. Ann Neurosci 25:25–37. CrossRefPubMedGoogle Scholar
  3. 3.
    Uddin MS, Stachowiak A, Mamun AA et al (2018) Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci 10:1-18.
  4. 4.
    Uddin MS, Mamun AA, Hossain MS et al (2016) Exploring the effect of Phyllanthus emblica L. on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: promising natural gift for the mitigation of Alzheimer’s disease. Ann Neurosci 23:218–229. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Uddin MS, Mamun AA, Labu ZK et al (2018) Autophagic dysfunction in Alzheimer’s disease: cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis. J Cell Physiol 234(6):8094–8112. CrossRefPubMedGoogle Scholar
  6. 6.
    Uddin MS, Al Mamun A, Kabir MT, et al (2018) Nootropic and anti-Alzheimer’s actions of medicinal plants: molecular insight into therapeutic potential to alleviate Alzheimer’s neuropathology. Mol Neurobiol 1–20.
  7. 7.
    Uddin MS, Mamun AA, Takeda S et al (2018) Analyzing the chance of developing dementia among geriatric people: a cross-sectional pilot study in Bangladesh. Psychogeriatrics. 19(2):87–94. CrossRefPubMedGoogle Scholar
  8. 8.
    Uddin MS, Amran MS (eds) (2018) Handbook of research on critical examinations of neurodegenerative disorders, 1st ed. USA: IGI Global.
  9. 9.
    Mamum AA, Uddin MS, Wahid F et al (2016) Neurodefensive effect of Olea europaea L. in alloxan-induced cognitive dysfunction and brain tissue oxidative stress in mice: incredible natural nootropic. J Neurol Neurosci 7:1-12.
  10. 10.
    Uddin MS, Mamun AA, Iqbal MA et al (2016) Analyzing nootropic effect of Phyllanthus reticulatus Poir. on cognitive functions, brain antioxidant enzymes and acetylcholinesterase activity against aluminium-induced Alzheimer’s model in rats: applicable for controlling the risk factors of Alzheimer’s disease. Adv Alzheimer’s Dis 05:87–102. CrossRefGoogle Scholar
  11. 11.
    Grandy JK (2013) Melatonin: therapeutic intervention in mild cognitive impairment and Alzheimer disease. J Neurol Neurophysiol 04:1–6. CrossRefGoogle Scholar
  12. 12.
    Uddin MS, Kabir MT, Al Mamun A et al (2018) APOE and Alzheimer’s disease: evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol 56(4):2450–2465. 1–16. CrossRefPubMedGoogle Scholar
  13. 13.
    ADI G8 (2050) Policy Briefing reveals 135 million people will live with dementia by Alzheimer’s Disease InternationalGoogle Scholar
  14. 14.
    Savaskan E, Ayoub MA, Ravid R et al (2005) Reduced hippocampal MT2 melatonin receptor expression in Alzheimer’s disease. J Pineal Res 38:10–16. CrossRefPubMedGoogle Scholar
  15. 15.
    Naseem M, Parvez S (2014) Role of melatonin in traumatic brain injury and spinal cord injury. Sci World J 2014:1–13. CrossRefGoogle Scholar
  16. 16.
    Wang L, Feng C, Zheng X et al (2017) Plant mitochondria synthesize melatonin and enhance the tolerance of plants to drought stress. J Pineal Res 63:e12429. CrossRefGoogle Scholar
  17. 17.
    Payne JK (2006) The trajectory of biomarkers in symptom management for older adults with cancer. Semin Oncol Nurs 22:31–35. CrossRefPubMedGoogle Scholar
  18. 18.
    Sugden D (1983) Psychopharmacological effects of melatonin in mouse and rat. J Pharmacol Exp Ther 227:587–591PubMedGoogle Scholar
  19. 19.
    Bilici D, Akpinar E, Kiziltunç A (2002) Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharmacol Res 46:133–139CrossRefPubMedGoogle Scholar
  20. 20.
    Carrillo-Vico A, Lardone P, Álvarez-Sánchez N et al (2013) Melatonin: buffering the immune system. Int J Mol Sci 14:8638–8683. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Srinivasan V, Pandi-Perumal SR, Spence DW et al (2010) Potential use of melatonergic drugs in analgesia: mechanisms of action. Brain Res Bull 81:362–371. CrossRefPubMedGoogle Scholar
  22. 22.
    Tan D-X, Manchester LC, Sanchez-Barcelo E et al (2010) Significance of high levels of endogenous melatonin in mammalian cerebrospinal fluid and in the central nervous system. Curr Neuropharmacol 8:162–167. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Benot S, Molinero P, Soutto M et al (1998) Circadian variations in the rat serum total antioxidant status: correlation with melatonin levels. J Pineal Res 25:1–4. CrossRefPubMedGoogle Scholar
  24. 24.
    Kasahara T, Abe K, Mekada K et al (2010) Genetic variation of melatonin productivity in laboratory mice under domestication. Proc Natl Acad Sci 107:6412–6417. CrossRefPubMedGoogle Scholar
  25. 25.
    Semenova NV, Madaeva IM, Bairova TA et al (2018) Association of the melatonin circadian rhythms with clock 3111T/C gene polymorphism in Caucasian and Asian menopausal women with insomnia. Chronobiol Int 35:1–11. CrossRefGoogle Scholar
  26. 26.
    Reiter RJ (1995) The pineal gland and melatonin in relation to aging: a summary of the theories and of the data. Exp Gerontol 30:199–212CrossRefPubMedGoogle Scholar
  27. 27.
    Reiter RJ, Tan DX, Poeggeler B et al (1994) Melatonin as a free radical scavenger: implications for aging and age-related diseases. Ann N Y Acad Sci 719:1–12CrossRefPubMedGoogle Scholar
  28. 28.
    Rosales-Corral S, Tan D-X, Reiter RJ et al (2003) Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. J Pineal Res 35:80–84CrossRefPubMedGoogle Scholar
  29. 29.
    Smith MA, Hirai K, Hsiao K et al (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215CrossRefPubMedGoogle Scholar
  30. 30.
    Wu Y-H, Feenstra MGP, Zhou J-N et al (2003) Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 88:5898–5906. CrossRefPubMedGoogle Scholar
  31. 31.
    Wu Y-H, Swaab DF (2005) The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 38:145–152. CrossRefPubMedGoogle Scholar
  32. 32.
    Rosales-Corral SA, Acuña-Castroviejo D, Coto-Montes A et al (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202. CrossRefPubMedGoogle Scholar
  33. 33.
    Lin L, Huang Q-X, Yang S-S et al (2013) Melatonin in Alzheimer’s disease. Int J Mol Sci 14:14575–14593. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Devi L, Prabhu BM, Galati DF et al (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Butterfield DA, Drake J, Pocernich C, Castegna A (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7:548–554CrossRefPubMedGoogle Scholar
  36. 36.
    Lahiri DK, Ghosh C (1999) Interactions between melatonin, reactive oxygen species, and nitric oxide. Ann N Y Acad Sci 893:325–330CrossRefPubMedGoogle Scholar
  37. 37.
    Matsubara E, Bryant-Thomas T, Pacheco Quinto J et al (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85:1101–1108. CrossRefPubMedGoogle Scholar
  38. 38.
    Lahiri DK, Chen D, Ge Y-W et al (2004) Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 36:224–231. CrossRefPubMedGoogle Scholar
  39. 39.
    Song W, Lahiri DK (1997) Melatonin alters the metabolism of the β-amyloid precursor protein in the neuroendocrine cell line PC12. J Mol Neurosci 9:75–92. CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang Y, Wang Z, Wang Q et al (2004) Melatonin attenuates beta-amyloid-induced inhibition of neurofilament expression. Acta Pharmacol Sin 25:447–451PubMedGoogle Scholar
  41. 41.
    Olivieri G, Hess C, Savaskan E et al (2001) Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 31:320–325CrossRefPubMedGoogle Scholar
  42. 42.
    Zhu LQ, Wang SH, Ling ZQ et al (2004) Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat. J Pineal Res 37:71–77. CrossRefPubMedGoogle Scholar
  43. 43.
    Corpas R, Griñán-Ferré C, Palomera-Ávalos V et al (2018) Melatonin induces mechanisms of brain resilience against neurodegeneration. J Pineal Res 65:e12515. CrossRefPubMedGoogle Scholar
  44. 44.
    Kang J-E, Lim MM, Bateman RJ et al (2009) Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science (80-) 326:1005–1007. CrossRefGoogle Scholar
  45. 45.
    Moe V, Larsen P (1995) Symposium: Cognitive processes and sleep disturbances: sleep/wake patterns in Alzheimer’s disease: relationships with cognition and function. J Sleep Res 4:15–20CrossRefPubMedGoogle Scholar
  46. 46.
    Brusco LI, Márquez M, Cardinali DP (1998) Monozygotic twins with Alzheimer’s disease treated with melatonin: case report. J Pineal Res 25:260–263CrossRefPubMedGoogle Scholar
  47. 47.
    Brusco L, Fainstein I, Márquez M, Cardinali D (1999) Effect of melatonin in selected populations of sleep-disturbed patients. Neurosignals 8:126–131. CrossRefGoogle Scholar
  48. 48.
    Brusco LI, Márquez M, Cardinali DP (2000) Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuro Endocrinol Lett 21:39–42PubMedGoogle Scholar
  49. 49.
    Poeggeler B, Miravalle L, Zagorski MG et al (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry 40:14995–15001CrossRefPubMedGoogle Scholar
  50. 50.
    Feng Z, Chang Y, Cheng Y et al (2004) Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer’s disease. J Pineal Res 37:129–136. CrossRefPubMedGoogle Scholar
  51. 51.
    Wang X-C, Zhang J, Yu X et al (2005) Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat. Sheng Li Xue Bao 57:7–12PubMedGoogle Scholar
  52. 52.
    McCurry SM, Reynolds CF, Ancoli-Israel S et al (2000) Treatment of sleep disturbance in Alzheimer’s disease. Sleep Med Rev 4:603–628. CrossRefPubMedGoogle Scholar
  53. 53.
    Lerner AB, Case JD, Takahashi Y et al (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes 1. J Am Chem Soc 80:2587–2587. CrossRefGoogle Scholar
  54. 54.
    Ueck M, Wake K (1977) The pinealocyte--a paraneuron? A review Arch Histol Jpn 40(Suppl):261–278CrossRefPubMedGoogle Scholar
  55. 55.
    Stehle JH, Saade A, Rawashdeh O et al (2011) A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 51:17–43. CrossRefPubMedGoogle Scholar
  56. 56.
    Yonei Y, Hattori A, Tsutsui K, et al (2010) Effects of melatonin: basics studies and clinical applicationsGoogle Scholar
  57. 57.
    Stokkan K-A, Reiter RJ (1994) Melatonin rhythms in Arctic urban residents. J Pineal Res 16:33–36. CrossRefPubMedGoogle Scholar
  58. 58.
    Sayler A, Wolfson A (1969) Hydroxyindole-o-methyl transferase (HIOMT) activity in the Japanese quail in relation to sexual maturation and light. Neuroendocrinology 5:322–332. CrossRefPubMedGoogle Scholar
  59. 59.
    Pévet P (2002) Melatonin. Dialogues Clin Neurosci 4:57–72PubMedPubMedCentralGoogle Scholar
  60. 60.
    Armstrong SM, Redman JR (1991) Melatonin: a chronobiotic with anti-aging properties? Med Hypotheses 34:300–309CrossRefPubMedGoogle Scholar
  61. 61.
    Kunz D (2004) Chronobiotic protocol and circadian sleep propensity index: new tools for clinical routine and research on melatonin and sleep. Pharmacopsychiatry 37:139–146. CrossRefPubMedGoogle Scholar
  62. 62.
    Maestroni GJ, Conti A (1989) Beta-endorphin and dynorphin mimic the circadian immunoenhancing and anti-stress effects of melatonin. Int J Immunopharmacol 11:333–340CrossRefPubMedGoogle Scholar
  63. 63.
    Benot S, Goberna R, Reiter RJ et al (1999) Physiological levels of melatonin contribute to the antioxidant capacity of human serum. J Pineal Res 27:59–64CrossRefPubMedGoogle Scholar
  64. 64.
    Yon J-H, Carter LB, Reiter RJ, Jevtovic-Todorovic V (2006) Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis 21:522–530. CrossRefPubMedGoogle Scholar
  65. 65.
    Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. J Pineal Res 55:N/a. CrossRefGoogle Scholar
  66. 66.
    Thomas JN, Smith-Sonneborn J (1997) Supplemental melatonin increases clonal lifespan in the protozoan Paramecium tetraurelia. J Pineal Res 23:123–130. CrossRefPubMedGoogle Scholar
  67. 67.
    Pierpaoli W, Dall’Ara A, Pedrinis E, Regelson W (1991) The pineal control of aging. The effects of melatonin and pineal grafting on the survival of older mice. Ann N Y Acad Sci 621:291–313CrossRefPubMedGoogle Scholar
  68. 68.
    Bonilla E, Medina-Leendertz S, Díaz S (2002) Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp Gerontol 37:629–638CrossRefPubMedGoogle Scholar
  69. 69.
    Masana MI, Dubocovich ML (2001) Melatonin receptor signaling: finding the path through the dark. Sci Signal 2001:pe39–pe39. CrossRefGoogle Scholar
  70. 70.
    Cristòfol R, Porquet D, Corpas R et al (2012) Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. J Pineal Res 52:271–281. CrossRefPubMedGoogle Scholar
  71. 71.
    Chang H-M, Wu U-I, Lan C-T (2009) Melatonin preserves longevity protein (sirtuin 1) expression in the hippocampus of total sleep-deprived rats. J Pineal Res 47:211–220. CrossRefPubMedGoogle Scholar
  72. 72.
    Wang J, Fivecoat H, Ho L et al (2010) The role of Sirt1: at the crossroad between promotion of longevity and protection against Alzheimer’s disease neuropathology. Biochim Biophys Acta, Proteins Proteomics 1804:1690–1694. CrossRefGoogle Scholar
  73. 73.
    Albani D, Polito L, Batelli S et al (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1-42) peptide. J Neurochem 110:1445–1456. CrossRefPubMedGoogle Scholar
  74. 74.
    Julien C, Tremblay C, Émond V et al (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68:48–58. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Qin W, Yang T, Ho L et al (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754. CrossRefPubMedGoogle Scholar
  76. 76.
    Tippmann F, Hundt J, Schneider A et al (2009) Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J 23:1643–1654. CrossRefPubMedGoogle Scholar
  77. 77.
    West RL, Lee JM, Maroun LE (1995) Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J Mol Neurosci 6:141–146. CrossRefPubMedGoogle Scholar
  78. 78.
    Ding H, Dolan PJ, Johnson GVW (2008) Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem 106:2119–2130. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Jenwitheesuk A, Nopparat C, Mukda S et al (2014) Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci 15:16848–16884. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Van Someren EJ (2000) Circadian and sleep disturbances in the elderly. Exp Gerontol 35:1229–1237CrossRefPubMedGoogle Scholar
  81. 81.
    Foley DJ, Monjan AA, Brown SL et al (1995) Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 18:425–432CrossRefPubMedGoogle Scholar
  82. 82.
    Huang Y-L, Liu R-Y, Wang Q-S et al (2002) Age-associated difference in circadian sleep-wake and rest-activity rhythms. Physiol Behav 76:597–603CrossRefPubMedGoogle Scholar
  83. 83.
    McCurry SM, Logsdon RG, Teri L et al (1999) Characteristics of sleep disturbance in community-dwelling Alzheimer’s disease patients. J Geriatr Psychiatry Neurol 12:53–59. CrossRefPubMedGoogle Scholar
  84. 84.
    Bonanni E, Maestri M, Tognoni G et al (2005) Daytime sleepiness in mild and moderate Alzheimer’s disease and its relationship with cognitive impairment. J Sleep Res 14:311–317. CrossRefPubMedGoogle Scholar
  85. 85.
    Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941. CrossRefPubMedGoogle Scholar
  86. 86.
    Haugh RM, Markesbery WR (1983) Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function. Arch Neurol 40:560–563CrossRefPubMedGoogle Scholar
  87. 87.
    Kalsbeek A, van Heerikhuize JJ, Wortel J, Buijs RM (1996) A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist. J Neurosci 16:5555–5565CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Hofman MA, Swaab DF (1995) Influence of aging on the seasonal rhythm of the vasopressin-expressing neurons in the human suprachiasmatic nucleus. Neurobiol Aging 16:965–971. CrossRefPubMedGoogle Scholar
  89. 89.
    Swaab DF, Roozendaal B, Ravid R et al (1987) Suprachiasmatic nucleus in aging, Alzheimer’s disease, transsexuality and Prader-Willi syndrome. Prog Brain Res 72:301–310CrossRefPubMedGoogle Scholar
  90. 90.
    Zhou J-N, Swaab DF (1999) Activation and degeneration during aging: a morphometric study of the human hypothalamus. Microsc Res Tech 44:36–48.<36::AID-JEMT5>3.0.CO;2-F CrossRefPubMedGoogle Scholar
  91. 91.
    Zhou JN, Hofman MA, Swaab DF VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol Aging 16:571–576Google Scholar
  92. 92.
    Swaab DF, Fliers E, Partiman TS (1985) The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 342:37–44CrossRefPubMedGoogle Scholar
  93. 93.
    Swaab DF, Grundke-Iqbal I, Iqbal K et al (1992) Tau and ubiquitin in the human hypothalamus in aging and Alzheimer’s disease. Brain Res 590:239–249CrossRefPubMedGoogle Scholar
  94. 94.
    Liu RY, Zhou JN, Hoogendijk WJ et al (2000) Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J Neuropathol Exp Neurol 59:314–322CrossRefPubMedGoogle Scholar
  95. 95.
    Lowrey PL, Takahashi JS (2000) Genetics of the mammalian circadian system: photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Annu Rev Genet 34:533–562. CrossRefPubMedGoogle Scholar
  96. 96.
    Yoo S-H, Yamazaki S, Lowrey PL et al (2004) PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci 101:5339–5346. CrossRefPubMedGoogle Scholar
  97. 97.
    Steeves TDL, King DP, Zhao Y et al (1999) Molecular cloning and characterization of the HumanCLOCKGene: expression in the suprachiasmatic nuclei. Genomics 57:189–200. CrossRefPubMedGoogle Scholar
  98. 98.
    Simonneaux V, Poirel V-J, Garidou M-L et al (2004) Daily rhythm and regulation of clock gene expression in the rat pineal gland. Brain Res Mol Brain Res 120:164–172CrossRefPubMedGoogle Scholar
  99. 99.
    Kolker DE, Fukuyama H, Huang DS et al (2003) Aging alters circadian and light-induced expression of clock genes in golden hamsters. J Biol Rhythm 18:159–169. CrossRefGoogle Scholar
  100. 100.
    Yamazaki S, Straume M, Tei H et al (2002) Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci 99:10801–10806. CrossRefPubMedGoogle Scholar
  101. 101.
    Claustrat B, Brun J, Chazot G (2005) The basic physiology and pathophysiology of melatonin. Sleep Med Rev 9:11–24. CrossRefPubMedGoogle Scholar
  102. 102.
    Wu Y-H, Fischer DF, Kalsbeek A et al (2006) Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock”. FASEB J 20:1874–1876. CrossRefPubMedGoogle Scholar
  103. 103.
    Song H, Moon M, Choe HK et al (2015) Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease. Mol Neurodegener 10:13. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185CrossRefPubMedGoogle Scholar
  105. 105.
    Ekmekcioglu C (2006) Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother 60:97–108. CrossRefPubMedGoogle Scholar
  106. 106.
    Weaver DR, Reppert SM (1996) The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport 8:109–112CrossRefPubMedGoogle Scholar
  107. 107.
    Thomas L, Purvis CC, Drew JE et al (2002) Melatonin receptors in human fetal brain: 2-[(125)I]iodomelatonin binding and MT1 gene expression. J Pineal Res 33:218–224CrossRefPubMedGoogle Scholar
  108. 108.
    Wu Y-H, Zhou J-N, Balesar R et al (2006) Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol 499:897–910. CrossRefPubMedGoogle Scholar
  109. 109.
    Wu Y-H, Zhou J-N, Van Heerikhuize J et al (2007) Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 28:1239–1247. CrossRefPubMedGoogle Scholar
  110. 110.
    Liu C, Weaver DR, Jin X et al (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91–102CrossRefPubMedGoogle Scholar
  111. 111.
    Zhou J-N, Liu R-Y, Kamphorst W et al (2003) Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35:125–130CrossRefPubMedGoogle Scholar
  112. 112.
    Liu R-Y, Zhou J-N, van Heerikhuize J et al (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-ε4/4 genotype 1. J Clin Endocrinol Metab 84:323–327. CrossRefPubMedGoogle Scholar
  113. 113.
    Reiter RJ, Tan DX, Manchester LC, El-Sawi MR (2002) Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Ann N Y Acad Sci 959:238–250CrossRefPubMedGoogle Scholar
  114. 114.
    Reiter RJ, Tan D, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. J Biomed Sci 7:444–458. CrossRefPubMedGoogle Scholar
  115. 115.
    Pappolla MA, Chyan Y-J, Poeggeler B et al (2000) An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm 107:203–231. CrossRefPubMedGoogle Scholar
  116. 116.
    Wang J, Wang Z (2006) Role of melatonin in Alzheimer-like neurodegeneration1. Acta Pharmacol Sin 27:41–49.
  117. 117.
    Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI (2003) Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci 8:d1093–d1108CrossRefPubMedGoogle Scholar
  118. 118.
    Reppert SM, Godson C, Mahle CD et al (1995) Molecular characterization of a second melatonin receptor expressed in human retina and brain: The Mel1b melatonin receptor. Proc Natl Acad Sci 92:8734–8738. CrossRefPubMedGoogle Scholar
  119. 119.
    Lockley SW, Skene DJ, James K et al (2000) Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 164:R1–R6CrossRefPubMedGoogle Scholar
  120. 120.
    Sack RL, Brandes RW, Kendall AR, Lewy AJ (2000) Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 343:1070–1077. CrossRefPubMedGoogle Scholar
  121. 121.
    Skene DJ (2003) Optimization of light and melatonin to phase-shift human circadian rhythms. J Neuroendocrinol 15:438–441CrossRefPubMedGoogle Scholar
  122. 122.
    Swaab DF (Dick F (2003) The human hypothalamus : basic and clinical aspects. ElsevierGoogle Scholar
  123. 123.
    Arendt J, Skene DJ, Middleton B et al (1997) Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythm 12:604–617. CrossRefGoogle Scholar
  124. 124.
    Duffy JF, Zeitzer JM, Czeisler CA (2007) Decreased sensitivity to phase-delaying effects of moderate intensity light in older subjects. Neurobiol Aging 28:799–807. CrossRefPubMedGoogle Scholar
  125. 125.
    Herljevic M, Middleton B, Thapan K, Skene D (2005) Light-induced melatonin suppression: age-related reduction in response to short wavelength light. Exp Gerontol 40:237–242. CrossRefGoogle Scholar
  126. 126.
    Shochat T, Martin J, Marler M, Ancoli-Israel S (2000) Illumination levels in nursing home patients: effects on sleep and activity rhythms. J Sleep Res 9:373–379CrossRefPubMedGoogle Scholar
  127. 127.
    Mishima K, Okawa M, Shimizu T, Hishikawa Y (2001) Diminished melatonin secretion in the elderly caused by insufficient environmental illumination 1. J Clin Endocrinol Metab 86:129–134. CrossRefPubMedGoogle Scholar
  128. 128.
    Ancoli-Israel S, Klauber MR, Jones DW et al (1997) Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients. Sleep 20:18–23CrossRefPubMedGoogle Scholar
  129. 129.
    Ohashi Y, Okamoto N, Uchida K et al (1999) Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer’s type. Biol Psychiatry 45:1646–1652CrossRefPubMedGoogle Scholar
  130. 130.
    Laurin D, Verreault R, Lindsay J et al (2001) Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 58:498–504CrossRefPubMedGoogle Scholar
  131. 131.
    Barnes LL, Mendes de Leon CF, Wilson RS et al (2004) Social resources and cognitive decline in a population of older African Americans and whites. Neurology 63:2322–2326CrossRefPubMedGoogle Scholar
  132. 132.
    Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112. CrossRefPubMedGoogle Scholar
  133. 133.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science (80- ) 298:789–791. CrossRefGoogle Scholar
  134. 134.
    He H, Dong W, Huang F (2010) Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Curr Neuropharmacol 8:211–217. CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Wang X-C, Zhang Y-C, Chatterjie N et al (2008) Effect of melatonin and melatonylvalpromide on β-amyloid and neurofilaments in N2a cells. Neurochem Res 33:1138–1144. CrossRefPubMedGoogle Scholar
  136. 136.
    Jin N, Yin X, Yu D et al (2015) Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer’s disease. Sci Rep 5:8187. CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    van Eersel J, Ke YD, Liu X et al (2010) Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc Natl Acad Sci 107:13888–13893. CrossRefPubMedGoogle Scholar
  138. 138.
    Shimohama S, Tanino H, Fujimoto S (1999) Changes in caspase expression in Alzheimer’s disease: comparison with development and aging. Biochem Biophys Res Commun 256:381–384. CrossRefPubMedGoogle Scholar
  139. 139.
    Tesco G, Koh YH, Kang EL et al (2007) Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54:721–737. CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Oh S, Gwak J, Park S, Yang CS (2014) Green tea polyphenol EGCG suppresses Wnt/β-catenin signaling by promoting GSK-3β- and PP2A-independent β-catenin phosphorylation/degradation. BioFactors 40:586–595. CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Yang C-C, Kuai X-X, Li Y-L et al (2013) Cornel iridoid glycoside attenuates tau hyperphosphorylation by inhibition of PP2A demethylation. Evid Based Complement Alternat Med 2013:108486. CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Louneva N, Cohen JW, Han L-Y et al (2008) Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol 173:1488–1495. CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Espino J, Bejarano I, Redondo PC et al (2010) Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: evidence for the involvement of mitochondria and Bax activation. J Membr Biol 233:105–118. CrossRefPubMedGoogle Scholar
  144. 144.
    Ling X, Zhang LM, Lu SD et al (1999) Protective effect of melatonin on injuried cerebral neurons is associated with bcl-2 protein over-expression. Zhongguo Yao Li Xue Bao 20:409–414PubMedGoogle Scholar
  145. 145.
    Jang M-H, Jung S-B, Lee M-H et al (2005) Melatonin attenuates amyloid beta25–35-induced apoptosis in mouse microglial BV2 cells. Neurosci Lett 380:26–31. CrossRefPubMedGoogle Scholar
  146. 146.
    Harada J, Sugimoto M (1999) Activation of caspase-3 in beta-amyloid-induced apoptosis of cultured rat cortical neurons. Brain Res 842:311–323CrossRefPubMedGoogle Scholar
  147. 147.
    Sahab Uddin M, Nasrullah M, Hossain MS et al (2016) Evaluation of nootropic activity of Persicaria flaccida on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: implication for the management of Alzheimer’s disease. Am J Psychiatry Neurosci 4:26. CrossRefGoogle Scholar
  148. 148.
    Uddin MS, Asaduzzaman M, Mamun AA, Iqbal MA, Wahid FRR (2016) Neuroprotective activity of Asparagus racemosus Linn. Against ethanol- induced cognitive impairment and oxidative stress in rats brain: auspicious for controlling the risk of Alzheimer’s disease. J Alzheimer’s Dis Park 6:1–10.
  149. 149.
    Gong Y-H, Hua N, Zang X et al (2018) Melatonin ameliorates Aβ 1-42-induced Alzheimer’s cognitive deficits in mouse model. J Pharm Pharmacol 70:70–80. CrossRefPubMedGoogle Scholar
  150. 150.
    O’Neal-Moffitt G, Delic V, Bradshaw PC, Olcese J (2015) Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice. Mol Neurodegener 10:27. CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247CrossRefPubMedGoogle Scholar
  152. 152.
    Shipton OA, Leitz JR, Dworzak J et al (2011) Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci 31:1688–1692. CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168CrossRefPubMedGoogle Scholar
  154. 154.
    Ferrer I, Gomez-Isla T, Puig B et al (2005) Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr Alzheimer Res 2:3–18CrossRefPubMedGoogle Scholar
  155. 155.
    Moreira PI, Honda K, Zhu X et al (2006) Brain and brawn: parallels in oxidative strength. Neurology 66:S97–S101.
  156. 156.
    Lee VM, Balin BJ, Otvos L, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251:675–678CrossRefPubMedGoogle Scholar
  157. 157.
    Khatoon S, Grundke-Iqbal I, Iqbal K (1992) Brain levels of microtubule-associated protein tau are elevated in Alzheimer’s disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem 59:750–753CrossRefPubMedGoogle Scholar
  158. 158.
    Khatoon S, Grundke-Iqbal I, Iqbal K (1994) Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett 351:80–84CrossRefPubMedGoogle Scholar
  159. 159.
    Costa EJ, Lopes RH, Lamy-Freund MT (1995) Permeability of pure lipid bilayers to melatonin. J Pineal Res 19:123–126CrossRefPubMedGoogle Scholar
  160. 160.
    Deng Y, Xu G, Duan P et al (2005) Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin 26:519–526. CrossRefPubMedGoogle Scholar
  161. 161.
    Pandi-Perumal SR, Cardinali DP (2007) Melatonin : from molecules to therapy. Nova Biomedical BooksGoogle Scholar
  162. 162.
    Peng C-X, Hu J, Liu D et al (2013) Disease-modified glycogen synthase kinase-3β intervention by melatonin arrests the pathology and memory deficits in an Alzheimer’s animal model. Neurobiol Aging 34:1555–1563. CrossRefPubMedGoogle Scholar
  163. 163.
    Feng Z, Qin C, Chang Y, Zhang J (2006) Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic Biol Med 40:101–109. CrossRefPubMedGoogle Scholar
  164. 164.
    Bhat RV, Budd Haeberlein SL, Avila J (2004) Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem 89:1313–1317. CrossRefPubMedGoogle Scholar
  165. 165.
    Eldar-Finkelman H (2002) Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med 8:126–132CrossRefPubMedGoogle Scholar
  166. 166.
    Li X, Bijur GN, Jope RS (2002) Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord 4:137–144CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Bhat RV, Budd SL (2002) GSK3beta signalling: casting a wide net in Alzheimer’s disease. Neurosignals 11:251–261. CrossRefPubMedGoogle Scholar
  168. 168.
    Krasilnikov MA (2000) Phosphatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry (Mosc) 65:59–67Google Scholar
  169. 169.
    Hoppe JB, Frozza RL, Horn AP et al (2010) Amyloid-β neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK-3β, tau and neuroinflammation. J Pineal Res 48:230–238. CrossRefPubMedGoogle Scholar
  170. 170.
    Wang J, Xiao X, Zhang Y et al (2012) Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res 53:77–90. CrossRefPubMedGoogle Scholar
  171. 171.
    Xue F, Shi C, Chen Q et al (2017) Melatonin mediates protective effects against kainic acid-induced neuronal death through safeguarding ER stress and mitochondrial disturbance. Front Mol Neurosci 10:49. CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Shi C, Zeng J, Li Z et al (2018) Melatonin mitigates kainic acid-induced neuronal tau hyperphosphorylation and memory deficits through alleviating ER stress. Front Mol Neurosci 11(5).
  173. 173.
    Medeiros R, Baglietto-Vargas D, LaFerla FM (2011) The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci Ther 17:514–524. CrossRefPubMedGoogle Scholar
  174. 174.
    Salminen A, Kauppinen A, Suuronen T et al (2009) ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation 6:41. CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Hoozemans JJM, Veerhuis R, Van Haastert ES et al (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110:165–172. CrossRefPubMedGoogle Scholar
  176. 176.
    Kim JS, Heo RW, Kim H et al (2014) Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death. J Neural Transm 121:1233–1243. CrossRefPubMedGoogle Scholar
  177. 177.
    Zhang X-M, Zhu J (2011) Kainic acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines. Curr Neuropharmacol 9:388–398. CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Fernández-Bachiller MI, Pérez C, Campillo NE et al (2009) Tacrine-melatonin hybrids as multifunctional agents for Alzheimer’s disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem 4:828–841. CrossRefPubMedGoogle Scholar
  179. 179.
    Spuch C, Antequera D, Isabel Fernandez-Bachiller M et al (2010) A new Tacrine–melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer’s disease. Neurotox Res 17:421–431. CrossRefPubMedGoogle Scholar
  180. 180.
    Lau WWI, Ng JKY, Lee MMK et al (2012) Interleukin-6 autocrine signaling mediates melatonin MT 1/2 receptor-induced STAT3 Tyr 705 phosphorylation. J Pineal Res 52:477–489. CrossRefPubMedGoogle Scholar
  181. 181.
    Shen Y, Zhang G, Liu L, Xu S (2007) Suppressive effects of melatonin on amyloid-β-induced glial activation in rat hippocampus. Arch Med Res 38:284–290. CrossRefPubMedGoogle Scholar
  182. 182.
    Paouri E, Tzara O, Kartalou G-I et al (2017) Peripheral tumor necrosis factor-alpha (TNF-α) modulates amyloid pathology by regulating blood-derived immune cells and glial response in the brain of AD/TNF transgenic mice. J Neurosci 37:5155–5171. CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 21:195–218CrossRefPubMedGoogle Scholar
  184. 184.
    Uddin MS, Kabir MT, Jakaria M, et al (2019) Endothelial PPARγ is crucial for averting age-related vascular dysfunction by stalling oxidative stress and ROCK. Neurotox Res
  185. 185.
    Begum MM, Islam A, Begum R et al (2019) Ethnopharmacological inspections of organic extract of Oroxylum indicum in rat models: a promising natural gift. Evidence-Based Complement Altern Med 2019:1–13. CrossRefGoogle Scholar
  186. 186.
    Hüll M, Berger M, Volk B, Bauer J (1996) Occurrence of interleukin-6 in cortical plaques of Alzheimer’s disease patients may precede transformation of diffuse into neuritic plaques. Ann N Y Acad Sci 777:205–212CrossRefPubMedGoogle Scholar
  187. 187.
    Campbell IL, Abraham CR, Masliah E et al (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90:10061–10065CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Strauss S, Bauer J, Ganter U et al (1992) Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Lab Investig 66:223–230PubMedGoogle Scholar
  189. 189.
    Selkoe DJ (1996) Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298CrossRefPubMedGoogle Scholar
  190. 190.
    Zhang L, Zhao B, Yew DT et al (1997) Processing of Alzheimer’s amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. Biochem Biophys Res Commun 235:845–848. CrossRefPubMedGoogle Scholar
  191. 191.
    Hsiao K, Chapman P, Nilsen S et al (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102CrossRefPubMedGoogle Scholar
  192. 192.
    Liu X, Xu Y, Chen S et al (2014) Rescue of proinflammatory cytokine-inhibited chondrogenesis by the antiarthritic effect of melatonin in synovium mesenchymal stem cells via suppression of reactive oxygen species and matrix metalloproteinases. Free Radic Biol Med 68:234–246. CrossRefPubMedGoogle Scholar
  193. 193.
    Anuthakoengkun A, Itharat A (2014) Inhibitory effect on nitric oxide production and free radical scavenging activity of Thai medicinal plants in osteoarthritic knee treatment. J Med Assoc Thail 97(Suppl 8):S116–S124Google Scholar
  194. 194.
    Guenther AL, Schmidt SI, Laatsch H et al (2005) Reactions of the melatonin metabolite AMK (N1-acetyl-5-methoxykynuramine) with reactive nitrogen species: formation of novel compounds, 3-acetamidomethyl-6-methoxycinnolinone and 3-nitro-AMK. J Pineal Res 39:251–260. CrossRefPubMedGoogle Scholar
  195. 195.
    Tan D, Reiter RJ, Manchester LC et al (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–197CrossRefPubMedGoogle Scholar
  196. 196.
    Antolín I, Rodríguez C, Saínz RM et al (1996) Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 10:882–890CrossRefPubMedGoogle Scholar
  197. 197.
    Shen YX, Xu SY, Wei W et al (2002) The protective effects of melatonin from oxidative damage induced by amyloid beta-peptide 25-35 in middle-aged rats. J Pineal Res 32:85–89CrossRefPubMedGoogle Scholar
  198. 198.
    Shen Y-X, Xu S-Y, Wei W et al (2002) Melatonin reduces memory changes and neural oxidative damage in mice treated with D-galactose. J Pineal Res 32:173–178CrossRefPubMedGoogle Scholar
  199. 199.
    Wakatsuki A, Okatani Y, Shinohara K et al (2001) Melatonin protects fetal rat brain against oxidative mitochondrial damage. J Pineal Res 30:22–28CrossRefPubMedGoogle Scholar
  200. 200.
    Smith MA, Sayre LM, Monnier VM, Perry G (1995) Radical AGEing in Alzheimer’s disease. Trends Neurosci 18:172–176CrossRefPubMedGoogle Scholar
  201. 201.
    Uddin MS, Mamun AA, Kabir MT, et al (2017) Neurochemistry of neurochemicals: messengers of brain functions. Journal of Intellectual Disability - Diagnosis and Treatment 5:137-151.
  202. 202.
    Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751. CrossRefPubMedGoogle Scholar
  203. 203.
    Weldon DT, Rogers SD, Ghilardi JR et al (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18:2161–2173CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Du Yan S, Zhu H, Fu J et al (1997) Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci U S A 94:5296–5301CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Yan SD, Roher A, Chaney M et al (2000) Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide. Biochim Biophys Acta 1502:145–157CrossRefPubMedGoogle Scholar
  206. 206.
    Perini G, Della-Bianca V, Politi V et al (2002) Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J Exp Med 195:907–918CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Walker DG, Lue L-F, Beach TG (2002) Increased expression of the urokinase plasminogen-activator receptor in amyloid beta peptide-treated human brain microglia and in AD brains. Brain Res 926:69–79CrossRefPubMedGoogle Scholar
  208. 208.
    Brandt R, Hundelt M, Shahani N (2005) Tau alteration and neuronal degeneration in tauopathies: mechanisms and models. Biochim Biophys Acta Mol basis Dis 1739:331–354. CrossRefGoogle Scholar
  209. 209.
    Takuma K, Yan SS, Stern DM, Yamada K (2005) Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer’s disease. J Pharmacol Sci 97:312–316CrossRefPubMedGoogle Scholar
  210. 210.
    Guermonprez L, Ducrocq C, Gaudry-Talarmain YM (2001) Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants. Mol Pharmacol 60:838–846PubMedGoogle Scholar
  211. 211.
    Hensley K, Carney JM, Mattson MP et al (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A 91:3270–3274CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Cardoso SM, Santana I, Swerdlow RH, Oliveira CR (2004) Mitochondria dysfunction of Alzheimer’s disease cybrids enhances Aβ toxicity. J Neurochem 89:1417–1426. CrossRefPubMedGoogle Scholar
  213. 213.
    Sheehan JP, Swerdlow RH, Miller SW et al (1997) Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. J Neurosci 17:4612–4622CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Swerdlow RH, Parks JK, Cassarino DS et al (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49:918–925CrossRefPubMedGoogle Scholar
  215. 215.
    Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1366:211–223CrossRefPubMedGoogle Scholar
  216. 216.
    Beal MF (2000) Oxidative metabolism. Ann N Y Acad Sci 924:164–169CrossRefPubMedGoogle Scholar
  217. 217.
    Thiffault C, Bennett JP (2005) Cyclical mitochondrial deltapsiM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/ca+2 exchange are reduced in Alzheimer’s disease cybrids. Mitochondrion 5:109–119. CrossRefPubMedGoogle Scholar
  218. 218.
    Trimmer PA, Keeney PM, Borland MK et al (2004) Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer’s disease worsen with passage in culture. Neurobiol Dis 15:29–39CrossRefPubMedGoogle Scholar
  219. 219.
    Haughey NJ, Liu D, Nath A et al (2002) Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid β-peptide by amyloid β-peptide. NeuroMolecular Med 1:125–136. CrossRefPubMedGoogle Scholar
  220. 220.
    Donovan MH, Yazdani U, Norris RD et al (2006) Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol 495:70–83. CrossRefPubMedGoogle Scholar
  221. 221.
    Wen PH, Hof PR, Chen X et al (2004) The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol 188:224–237. CrossRefPubMedGoogle Scholar
  222. 222.
    Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85. CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Hamilton A, Holscher C (2012) The effect of ageing on neurogenesis and oxidative stress in the APPswe/PS1deltaE9 mouse model of Alzheimer’s disease. Brain Res 1449:83–93. CrossRefPubMedGoogle Scholar
  224. 224.
    Rodríguez JJ, Jones VC, Tabuchi M et al (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One 3:e2935. CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Martinez-Canabal A (2014) Reconsidering hippocampal neurogenesis in Alzheimer’s disease. Front Neurosci 8:147. CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    Haughey NJ, Nath A, Chan SL et al (2002) Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem 83:1509–1524CrossRefPubMedGoogle Scholar
  227. 227.
    Ghosal K, Stathopoulos A, Pimplikar SW (2010) APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One 5:e11866. CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Porayette P, Gallego MJ, Kaltcheva MM et al (2009) Differential processing of amyloid-β precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J Biol Chem 284:23806–23817. CrossRefPubMedPubMedCentralGoogle Scholar
  229. 229.
    Phiel CJ, Wilson CA, Lee VM-Y, Klein PS (2003) GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature 423:435–439. CrossRefPubMedGoogle Scholar
  230. 230.
    Zhou F, Zhang L, Wang A et al (2008) The association of GSK3β with E2F1 facilitates nerve growth factor-induced neural cell differentiation. J Biol Chem 283:14506–14515. CrossRefPubMedGoogle Scholar
  231. 231.
    Lie D-C, Colamarino SA, Song H-J et al (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370–1375. CrossRefPubMedGoogle Scholar
  232. 232.
    Anderton BH, Dayanandan R, Killick R, Lovestone S (2000) Does dysregulation of the notch and wingless/Wnt pathways underlie the pathogenesis of Alzheimer’s disease? Mol Med Today 6:54–59CrossRefPubMedGoogle Scholar
  233. 233.
    Alvarez AR, Godoy JA, Mullendorff K et al (2004) Wnt-3a overcomes β-amyloid toxicity in rat hippocampal neurons. Exp Cell Res 297:186–196. CrossRefPubMedGoogle Scholar
  234. 234.
    Ramírez-Rodríguez G, Vega-Rivera NM, Benítez-King G et al (2012) Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice. Neurosci Lett 530:53–58. CrossRefPubMedGoogle Scholar
  235. 235.
    Lacoste B, Angeloni D, Dominguez-Lopez S et al (2015) Anatomical and cellular localization of melatonin MT 1 and MT 2 receptors in the adult rat brain. J Pineal Res 58:397–417. CrossRefPubMedGoogle Scholar
  236. 236.
    Domínguez-Alonso A, Ramírez-Rodríguez G, Benítez-King G (2012) Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures. J Pineal Res 52:427–436. CrossRefPubMedGoogle Scholar
  237. 237.
    Liu J, Somera-Molina KC, Hudson RL, Dubocovich ML (2013) Melatonin potentiates running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeN mice hippocampus. J Pineal Res 54:222–231. CrossRefPubMedGoogle Scholar
  238. 238.
    Hong Y, Palaksha KJ, Park K et al (2010) REVIEW ARTICLE: Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury. J Pineal Res 49:201–209. CrossRefPubMedGoogle Scholar
  239. 239.
    Moriya T, Horie N, Mitome M, Shinohara K (2007) Melatonin influences the proliferative and differentiative activity of neural stem cells. J Pineal Res 42:411–418. CrossRefPubMedGoogle Scholar
  240. 240.
    Ramírez-Rodríguez G, Klempin F, Babu H et al (2009) Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 34:2180–2191. CrossRefPubMedGoogle Scholar
  241. 241.
    De Butte M, Pappas BA (2007) Pinealectomy causes hippocampal CA1 and CA3 cell loss: reversal by melatonin supplementation. Neurobiol Aging 28:306–313. CrossRefPubMedGoogle Scholar
  242. 242.
    Rennie K, De Butte M, Pappas BA (2009) Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat. J Pineal Res 47:313–317. CrossRefPubMedGoogle Scholar
  243. 243.
    Tocharus C, Puriboriboon Y, Junmanee T et al (2014) Melatonin enhances adult rat hippocampal progenitor cell proliferation via ERK signaling pathway through melatonin receptor. Neuroscience 275:314–321. CrossRefPubMedGoogle Scholar
  244. 244.
    Sotthibundhu A, Phansuwan-Pujito P, Govitrapong P (2010) Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone. J Pineal Res 49:291–300. CrossRefPubMedGoogle Scholar
  245. 245.
    McArthur AJ, Hunt AE, Gillette MU (1997) Melatonin action and signal transduction in the rat suprachiasmatic circadian clock: activation of protein kinase C at dusk and Dawn 1. Endocrinology 138:627–634. CrossRefPubMedGoogle Scholar
  246. 246.
    Shukla M, Htoo HH, Wintachai P et al (2015) Melatonin stimulates the nonamyloidogenic processing of β APP through the positive transcriptional regulation of ADAM10 and ADAM17. J Pineal Res 58:151–165. CrossRefPubMedGoogle Scholar
  247. 247.
    Agrawal R, Tyagi E, Shukla R, Nath C (2008) Effect of insulin and melatonin on acetylcholinesterase activity in the brain of amnesic mice. Behav Brain Res 189:381–386. CrossRefPubMedGoogle Scholar
  248. 248.
    Ishida A, Furukawa K, Keller JN, Mattson MP (1997) Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport 8:2133–2137CrossRefPubMedGoogle Scholar
  249. 249.
    Yuan T-F, Gu S, Shan C et al (2015) Oxidative stress and adult neurogenesis. Stem Cell Rev Rep 11:706–709. CrossRefPubMedGoogle Scholar
  250. 250.
    Sarlak G, Jenwitheesuk A, Chetsawang B, Govitrapong P (2013) Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration. J Pharmacol Sci 123:9–24CrossRefPubMedGoogle Scholar
  251. 251.
    Uchida K, Okamoto N, Ohara K, Morita Y (1996) Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res 717:154–159CrossRefPubMedGoogle Scholar
  252. 252.
    Skene DJ, Vivien-Roels B, Sparks DL et al (1990) Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease. Brain Res 528:170–174CrossRefPubMedGoogle Scholar
  253. 253.
    Mishima K, Tozawa T, Satoh K et al (1999) Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep–waking. Biol Psychiatry 45:417–421. CrossRefPubMedGoogle Scholar
  254. 254.
    Skene DJ, Swaab DF Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol 38:199–206Google Scholar
  255. 255.
    Reiter RJ, Tan D-X (2002) Role of CSF in the transport of melatonin. J Pineal Res 33:61CrossRefPubMedGoogle Scholar
  256. 256.
    Reiter RJ (1993) The melatonin rhythm: both a clock and a calendar. Experientia 49:654–664CrossRefPubMedGoogle Scholar
  257. 257.
    Cardinali DP, Brusco LI, Liberczuk C, Furio AM (2002) The use of melatonin in Alzheimer’s disease. Neuro Endocrinol Lett 23(Suppl 1):20–23PubMedGoogle Scholar
  258. 258.
    Cardinali DP, Furio AM, Brusco LI (2010) Clinical aspects of melatonin intervention in Alzheimer’s disease progression. Curr Neuropharmacol 8:218–227. CrossRefPubMedPubMedCentralGoogle Scholar
  259. 259.
    Magri F, Locatelli M, Balza G et al (1997) Changes in endocrine orcadian rhythms as markers of physiological and pathological brain aging. Chronobiol Int 14:385–396. CrossRefPubMedGoogle Scholar
  260. 260.
    Mahlberg R, Kunz D, Sutej I et al (2004) Melatonin treatment of day-night rhythm disturbances and sundowning in Alzheimer disease: an open-label pilot study using actigraphy. J Clin Psychopharmacol 24:456–459CrossRefPubMedGoogle Scholar
  261. 261.
    Asayama K, Yamadera H, Ito T et al (2003) Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 70:334–341CrossRefPubMedGoogle Scholar
  262. 262.
    Hardeland R (2005) Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 27:119–130CrossRefPubMedGoogle Scholar
  263. 263.
    Gunasingh Masilamoni J, Philip Jesudason E, Dhandayuthapani S et al (2008) The neuroprotective role of melatonin against amyloid β peptide injected mice. Free Radic Res 42:661–673. CrossRefPubMedGoogle Scholar
  264. 264.
    Husson I, Mesplès B, Bac P et al (2002) Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge. Ann Neurol 51:82–92CrossRefPubMedGoogle Scholar
  265. 265.
    Zhu G, Wang D, Lin Y-H et al (2001) Protein kinase C ϵ suppresses Aβ production and promotes activation of α-secretase. Biochem Biophys Res Commun 285:997–1006. CrossRefPubMedGoogle Scholar
  266. 266.
    Luo Y, Packer L (2006) Oxidative stress and age-related neurodegeneration. CRC/Taylor & FrancisGoogle Scholar
  267. 267.
    Pappolla MA, Sos M, Omar RA et al (1997) Melatonin prevents death of neuroblastoma cells exposed to the {Alzheimer} amyloid peptide. J Neurosci 17:1683–1690CrossRefPubMedPubMedCentralGoogle Scholar
  268. 268.
    Guerrero-Muñoz MJ, Castillo-Carranza DL, Kayed R (2014) Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins. Biochem Pharmacol 88:468–478. CrossRefPubMedGoogle Scholar
  269. 269.
    Sengupta U, Nilson AN, Kayed R (2016) The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6:42–49. CrossRefPubMedPubMedCentralGoogle Scholar
  270. 270.
    Walsh DM, Tseng BP, Rydel RE et al (2000) The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39:10831–10839CrossRefPubMedGoogle Scholar
  271. 271.
    Glabe CG (2006) Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 27:570–575. CrossRefPubMedGoogle Scholar
  272. 272.
    Chen Y-R, Glabe CG (2006) Distinct early folding and aggregation properties of Alzheimer amyloid-β peptides Aβ40 and Aβ42. J Biol Chem 281:24414–24422. CrossRefPubMedGoogle Scholar
  273. 273.
    Stys PK, You H, Zamponi GW (2012) Copper-dependent regulation of NMDA receptors by cellular prion protein: Implications for neurodegenerative disorders. J Physiol 590:1357–1368. CrossRefPubMedPubMedCentralGoogle Scholar
  274. 274.
    Gu Z, Liu W, Yan Z (2009) β-Amyloid impairs AMPA receptor trafficking and function by reducing ca 2+ /calmodulin-dependent protein kinase II synaptic distribution. J Biol Chem 284:10639–10649. CrossRefPubMedPubMedCentralGoogle Scholar
  275. 275.
    Pappolla M, Bozner P, Soto C et al (1998) Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273:7185–7188CrossRefPubMedGoogle Scholar
  276. 276.
    Poirier J, Davignon J, Bouthillier D et al (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet (London, England) 342:697–699CrossRefGoogle Scholar
  277. 277.
    Bazoti FN, Tsarbopoulos A, Markides KE, Bergquist J (2005) Study of the non-covalent interaction between amyloid-β-peptide and melatonin using electrospray ionization mass spectrometry. J Mass Spectrom 40:182–192. CrossRefPubMedGoogle Scholar
  278. 278.
    Johnstone M, Gearing AJ, Miller KM (1999) A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 93:182–193CrossRefPubMedGoogle Scholar
  279. 279.
    Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 24:1029–1046CrossRefPubMedGoogle Scholar
  280. 280.
    Li S, Hong S, Shepardson NE et al (2009) Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801. CrossRefPubMedPubMedCentralGoogle Scholar
  281. 281.
    Palop JJ, Mucke L (2010) Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818. CrossRefPubMedPubMedCentralGoogle Scholar
  282. 282.
    Liu D, Yang Q, Li S (2013) Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons. Brain Res Bull 93:10–16. CrossRefPubMedGoogle Scholar
  283. 283.
    Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. CrossRefPubMedGoogle Scholar
  284. 284.
    Cardinali DP, Golombek DA, Rosenstein RE et al (1997) Melatonin site and mechanism of action: single or multiple? J Pineal Res 23:32–39. CrossRefPubMedGoogle Scholar
  285. 285.
    Corrales A, Vidal R, García S et al (2014) Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model of Down syndrome. J Pineal Res 56:51–61. CrossRefPubMedGoogle Scholar
  286. 286.
    Thiel G (1993) Synapsin I, synapsin II, and synaptophysin: marker proteins of synaptic vesicles. Brain Pathol 3:87–95CrossRefPubMedGoogle Scholar
  287. 287.
    Ikeno T, Nelson RJ (2015) Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters. Hippocampus 25:142–148. CrossRefPubMedGoogle Scholar
  288. 288.
    Rudnitskaya EA, Muraleva NA, Maksimova KY et al (2015) Melatonin attenuates memory impairment, amyloid-β accumulation, and neurodegeneration in a rat model of sporadic Alzheimer’s disease. J Alzheimers Dis 47:103–116. CrossRefPubMedGoogle Scholar
  289. 289.
    Benleulmi-Chaachoua A, Chen L, Sokolina K et al (2016) Protein interactome mining defines melatonin MT 1 receptors as integral component of presynaptic protein complexes of neurons. J Pineal Res 60:95–108. CrossRefPubMedGoogle Scholar
  290. 290.
    Liu D, Wei N, Man H-Y et al (2015) The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling. Cell Death Differ 22:583–596. CrossRefPubMedGoogle Scholar
  291. 291.
    Ali T, Badshah H, Kim TH, Kim MO (2015) Melatonin attenuates D-galactose-induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF- K B/JNK signaling pathway in aging mouse model. J Pineal Res 58:71–85. CrossRefPubMedGoogle Scholar
  292. 292.
    Yoo DY, Kim W, Lee CH et al (2012) Melatonin improves d-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression. J Pineal Res 52:21–28. CrossRefPubMedGoogle Scholar
  293. 293.
    Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16:439–444CrossRefPubMedGoogle Scholar
  294. 294.
    Melo JB, Agostinho P, Oliveira CR (2003) Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 45:117–127CrossRefGoogle Scholar
  295. 295.
    Wang J-Y, Wen L-L, Huang Y-N et al (2006) Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr Pharm Des 12:3521–3533CrossRefPubMedGoogle Scholar
  296. 296.
    Lu J, Zheng Y-L, Wu D-M et al (2007) Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by d-galactose. Biochem Pharmacol 74:1078–1090. CrossRefPubMedGoogle Scholar
  297. 297.
    Mallidis C, Agbaje I, Rogers D et al (2007) Distribution of the receptor for advanced glycation end products in the human male reproductive tract: prevalence in men with diabetes mellitus. Hum Reprod 22:2169–2177. CrossRefPubMedGoogle Scholar
  298. 298.
    Chetsawang B, Govitrapong P, Ebadi M (2004) The neuroprotective effect of melatonin against the induction of c-Jun phosphorylation by 6-hydroxydopamine on SK-N-SH cells. Neurosci Lett 371:205–208. CrossRefPubMedGoogle Scholar
  299. 299.
    Feng Z, Zhang J (2005) Long-term melatonin or 17beta-estradiol supplementation alleviates oxidative stress in ovariectomized adult rats. Free Radic Biol Med 39:195–204. CrossRefPubMedGoogle Scholar
  300. 300.
    León J, Escames G, Rodríguez MI et al (2006) Inhibition of neuronal nitric oxide synthase activity by N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin. J Neurochem 98:2023–2033. CrossRefPubMedGoogle Scholar
  301. 301.
    Deng W-G, Tang S-T, Tseng H-P, Wu KK (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518–524. CrossRefPubMedPubMedCentralGoogle Scholar
  302. 302.
    Wang X, Zheng W, Xie J-W et al (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46. CrossRefPubMedPubMedCentralGoogle Scholar
  303. 303.
    Chung S-Y, Han S-H (2003) Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition. J Pineal Res 34:95–102CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Physical TherapyGraduate School of Inje UniversityGimhaeSouth Korea
  2. 2.Department of PharmacySoutheast UniversityDhakaBangladesh
  3. 3.Pharmakon Neuroscience Research NetworkDhakaBangladesh
  4. 4.Department of Rehabilitation ScienceGraduate School of Inje UniversityGimhaeSouth Korea
  5. 5.Departamento de Nutrición y Bioquímica, Facultad de CienciasPontificia Universidad JaverianaBogotá DCColombia
  6. 6.Instituto de Ciencias BiomédicasUniversidad Autónoma de ChileSantiagoChile
  7. 7.Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical ChemistryAhalia School of PharmacyPalakkadIndia
  8. 8.King Fahd Medical Research CenterKing Abdulaziz UniversityJeddahSaudi Arabia
  9. 9.Department of Medical Laboratory Technology, Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia

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