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Elevated Oxidative Stress and Decreased Antioxidant Function in the Human Hippocampus and Frontal Cortex with Increasing Age: Implications for Neurodegeneration in Alzheimer’s Disease

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Abstract

Oxidative stress and mitochondrial damage are implicated in the evolution of neurodegenerative diseases. Increased oxidative damage in specific brain regions during aging might render the brain susceptible to degeneration. Previously, we demonstrated increased oxidative damage and lowered antioxidant function in substantia nigra during aging making it vulnerable to degeneration associated with Parkinson’s disease. To understand whether aging contributes to the vulnerability of brain regions in Alzheimer’s disease, we assessed the oxidant and antioxidant markers, glutathione (GSH) metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I (CI) activity in hippocampus (HC) and frontal cortex (FC) compared with cerebellum (CB) in human brains with increasing age (0.01–80 years). We observed significant increase in protein oxidation (HC: p = 0.01; FC: p = 0.0002) and protein nitration (HC: p = 0.001; FC: p = 0.02) and increased GFAP expression (HC: p = 0.03; FC: p = 0.001) with a decreasing trend in CI activity in HC and FC compared to CB with increasing age. These changes were associated with a decrease in antioxidant enzyme activities, such as superoxide dismutase (HC: p = 0.005), catalase (HC: p = 0.02), thioredoxin reductase (FC: p = 0.04), GSH reductase (GR) (HC: p = 0.005), glutathione-s-transferase (HC: p = 0.0001; FC: p = 0.03) and GSH (HC: p = 0.01) with age. However, these parameters were relatively unaltered in CB. We suggest that the regions HC and FC are subjected to widespread oxidative stress, loss of antioxidant function and enhanced GFAP expression during aging which might make them more susceptible to deranged physiology and selective neuronal degeneration.

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Abbreviations

HC:

Hippocampus

FC:

Frontal cortex

CB:

Cerebellum

AD:

Alzheimer’s disease

PMI:

Postmortem interval

MCI:

Mild cognitive impairment

SOD:

Superoxide dismutase

GSH:

Glutathione

GR:

Glutathione reductase

GPx:

Glutathione peroxidase

GST:

Glutathione-s-transferase

GFAP:

Glial fibrillay acidic protein

GCL:

Glutamylcysteine ligase

ThrR:

Thioredoxin reductase

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Acknowledgments

The authors thank the Human Brain Tissue Repository (HBTR), NIMHANS, Bangalore, India, for providing the human brain tissue samples required for the study. This study was financially supported by a grant from the Indian Council of Medical Research (ICMR IRIS ID No. 2009-07710) (to MMSB). VC gratefully acknowledges the financial support from Sri Siddhartha Medical College, Tumkur, India. GH is supported by a senior research fellowship from ICMR, India. The authors gratefully acknowledge the donors and their relatives for the kind gift of human brains for neurobiological studies.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), No. 2900, Hosur Road, Bangalore, 560029, Karnataka, India

    C. Venkateshappa, G. Harish & M. M. Srinivas Bharath

  2. Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, 560029, India

    Anita Mahadevan & S. K. Shankar

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  1. C. Venkateshappa
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  2. G. Harish
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Correspondence to M. M. Srinivas Bharath.

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Venkateshappa, C., Harish, G., Mahadevan, A. et al. Elevated Oxidative Stress and Decreased Antioxidant Function in the Human Hippocampus and Frontal Cortex with Increasing Age: Implications for Neurodegeneration in Alzheimer’s Disease. Neurochem Res 37, 1601–1614 (2012). https://doi.org/10.1007/s11064-012-0755-8

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