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Cellular and Molecular Neurobiology

, Volume 34, Issue 7, pp 925–949 | Cite as

Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

  • Roberto Rodrigues
  • Robert B. Petersen
  • George Perry
Review Paper

Abstract

The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer’s disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic–pituitary axis, the hypothalamic–pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and “oxidopamatergic” cascades when triggered by psychosocial stress, severe life-threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression, these cascades may result in chronic depression–anxiety–stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to AD, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e., increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD-associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e., hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e., GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.

Keywords

Alzheimer’s disease Amyloid β Lipid peroxidation Major depressive disorder Nucleic acid oxidation Oxidative stress Tau 

Abbreviations

AD

Alzheimer’s disease

Amyloid-β

ACTH

Adrenal corticotrophic hormone

AGE

Advanced glycation end product

ApoEε4

Apolipoprotein Eε4

AβPP

Amyloid β protein precursor

BDNF

Brain-derived neurotrophic factor

CSF

Cerebral spinal fluid

DNA

Deoxyribonucleic acid

GSK-3β

Glycogen synthase kinase-β

GRH

Gonadotropin-releasing hormone

G-Px

Glutathione peroxidase

4-HNE

4-hydroxy-nonenal

HSP

Heat shock protein

5-HTT

Serotonin transporter

IL-1β

Interleucine-1β

IFN-γ

Interferon-γ

IL-1

Interleukin-1

IL-6R

Interleukin-6 receptor

JAK

Janus kinase

JNK 1–3

Jun NH2 kinases 1–3

MAPK

Mitogen-activated protein kinase

MCI

Mild cognitive impairment

MDD

Major depressive disorder

NGF

Nerve growth factor

NFT

Neurofibrillary tangle

NMDA

N-Methyl-dextro-aspartate

NMDAR

NMDA receptor

NO

Nitric oxide

NSAID

Non-steroidal anti-inflammatory drugs

NSD

Not senile dementia

PET

Positron emission tomography

PKC

Protein kinase C

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

SDAT

Senile dementia of Alzheimer type

SP

Senile plaque

Tau

Tau protein

TNF-ɑ

Tumor necrosis factor-ɑ

TRK-β

Tyrosine-receptor kinase-β

Notes

Acknowledgments

George Perry is supported by the Semmes Foundation, Inc.; the Alzheimer Association; and by a grant from the National Institute on Minority Health and Health Disparities (G12MD007591) from the National Institutes of Health.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Roberto Rodrigues
    • 1
  • Robert B. Petersen
    • 2
  • George Perry
    • 3
  1. 1.College of SciencesThe University of Texas at San AntonioSan AntonioUSA
  2. 2.Department of PathologyCase Western Reserve UniversityClevelandUSA
  3. 3.Department of BiologyThe University of Texas at San Antonio,College of SciencesSan AntonioUSA

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