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

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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.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

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

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Acknowledgments

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

Funding

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

Author information

Authors and Affiliations

  1. Department of Physical Therapy, Graduate School of Inje University, Gimhae, South Korea

    Md. Farhad Hossain

  2. Department of Pharmacy, Southeast University, Dhaka, Bangladesh

    Md. Sahab Uddin, G. M. Sala Uddin & Md. Siddiqul Islam

  3. Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

    Md. Sahab Uddin

  4. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, South Korea

    Dewan Md. Sumsuzzman

  5. Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá DC, Colombia

    George E. Barreto

  6. Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile

    George E. Barreto

  7. Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India

    Bijo Mathew

  8. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  9. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

Authors
  1. Md. Farhad Hossain
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  2. Md. Sahab Uddin
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  3. G. M. Sala Uddin
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  4. Dewan Md. Sumsuzzman
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  5. Md. Siddiqul Islam
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  6. George E. Barreto
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  7. Bijo Mathew
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  8. Ghulam Md Ashraf
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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.

Corresponding authors

Correspondence to Md. Sahab Uddin or Ghulam Md Ashraf.

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Hossain, M.F., Uddin, M.S., Uddin, G.M.S. et al. Melatonin in Alzheimer’s Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer’s Neuropathology. Mol Neurobiol 56, 8255–8276 (2019). https://doi.org/10.1007/s12035-019-01660-3

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  • DOI: https://doi.org/10.1007/s12035-019-01660-3

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