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


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.


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



Alzheimer’s disease



Adrenal corticotrophic hormone


Advanced glycation end product


Apolipoprotein Eε4


Amyloid β protein precursor


Brain-derived neurotrophic factor


Cerebral spinal fluid


Deoxyribonucleic acid


Glycogen synthase kinase-β


Gonadotropin-releasing hormone


Glutathione peroxidase




Heat shock protein


Serotonin transporter








Interleukin-6 receptor


Janus kinase

JNK 1–3

Jun NH2 kinases 1–3


Mitogen-activated protein kinase


Mild cognitive impairment


Major depressive disorder


Nerve growth factor


Neurofibrillary tangle




NMDA receptor


Nitric oxide


Non-steroidal anti-inflammatory drugs


Not senile dementia


Positron emission tomography


Protein kinase C


Reactive nitrogen species


Reactive oxygen species


Senile dementia of Alzheimer type


Senile plaque


Tau protein


Tumor necrosis factor-ɑ


Tyrosine-receptor kinase-β



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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