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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
Article

Abstract

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.

Keywords

Melatonin Alzheimer’s disease Amyloid β Neurofibrillary tangles Circadian rhythm 

Abbreviations

AD

Alzheimer’s disease

amyloid β

APP

amyloid protein precursor

AANAT

N-acetylserotonin by arylalkylamine N-acetyltransferase

AVP

arginine vasopressin

ACh

acetylcholine

AChE

acetylcholinesterase

AGEs

advanced glycation end products

ADAM10

a disintegrin and metalloproteinase domain-containing protein-10

AAD

aromatic amino acid decarboxylase

BMAL1

brain muscle ARNT-like 1

CSF

cerebrospinal fluid

CRY

cryptochrome

CLOCK

circadian locomotor output cycles kaput

COX2

cyclooxygenase-2

ChAT

choline acetyltransferase

C1q

complement 1q

CuZnSOD

copper-zinc superoxide dismutase

CDK5

cyclin-dependent kinase 5

ER

endoplasmic reticulum

GPx

glutathione peroxidase

H2O2

hydrogen peroxide

HIOMT

hydroxyindole-O-methyltransferase

IL1-β

interleukin-1-β

IL6

interleukin-6

KA

kainic acid

LPS

lipopolysaccharide

LTP

long-term potentiation

LTD

long-term depression

MCI

mild cognitive impairment

MnSOD

manganese superoxide dismutase

NFTs

neurofibrillary tangles

NO

nitric oxide

NOS2

nitric oxide synthase 2

NF-κB

nuclear factor kappa beta

PLC

phospholipase C

PKC

protein kinase C

PI3K

phosphatidylinositol 3-kinase

PER

period circadian protein homologue

PSEN1

presenilin-1

PSEN2

presenilin-2

ROS

reactive oxygen species

RHT

retinohypothalamic tract

SOD

superoxide dismutase

SCN

suprachiasmatic nucleus

SCG

superior cervical ganglion

SIRT1

sirtuin 1

TNF-α

tumor necrosis factor-α

VIP

vasoactive intestinal peptide

5-HTP

5-hydroxytryptophan

Bcl2

B cell lymphoma 2

PP2A

protein phosphatase 2A

GSK3β

glycogen synthase kinase 3 beta

PKA

protein kinase-A

Bax

BCL2 associated X

Par-4

prostate apoptosis response-4

JNK

c-JUN N-terminal kinase

ERK

extracellular signal-regulated kinase

MAO-A

monoamine oxidase A

RAGE

receptor for advanced glycation end products

GFAP

glial fibrillary acidic protein

Iba1

ionized calcium binding adaptor molecule 1

APOE

apolipoprotein E

PARP1

poly(ADP-ribose) polymerase-1

Notes

Acknowledgments

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.

Funding

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.

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© 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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