Academic journal article Indian Journal of Psychiatry

New Evidence on Iron, Copper Accumulation and Zinc Depletion and Its Correlation with DNA Integrity in Aging Human Brain Regions

Academic journal article Indian Journal of Psychiatry

New Evidence on Iron, Copper Accumulation and Zinc Depletion and Its Correlation with DNA Integrity in Aging Human Brain Regions

Article excerpt

Byline: P. Vasudevaraju, Bharathi, T. Jyothsna, N. Shamasundar, Subba. Rao, B. Balaraj, KSJ. Rao, T. Sathyanarayana Rao

Deoxyribonucleic acid (DNA) conformation and stability play an important role in brain function. Earlier studies reported alterations in DNA integrity in the brain regions of neurological disorders like Parkinson's and Alzheimer's diseases. However, there are only limited studies on DNA stability in an aging brain and the factors responsible for genomic instability are still not clear. In this study, we assess the levels of Copper (Cu), Iron (Fe) and Zinc (Zn) in three age groups (Group I: below 40 years), Group II: between 41-60 years) and Group III: above 61 years) in hippocampus and frontal cortex regions of normal brains. The number of samples in each group was eight. Genomic DNA was isolated and DNA integrity was studied by nick translation studies and presented as single and double strand breaks. The number of single strand breaks correspondingly increased with aging compared to double strand breaks. The strand breaks were more in frontal cortex compared to hippocampus. We observed that the levels of Cu and Fe are significantly elevated while Zn is significantly depleted as one progresses from Group I to Group III, indicating changes with aging in frontal cortex and hippocampus. But the elevation of metals was more in frontal cortical region compared to hippocampal region. There was a clear correlation between Cu and Fe levels versus strand breaks in aging brain regions. This indicates that genomic instability is progressive with aging and this will alter the gene expressions. To our knowledge, this is a new comprehensive database to date, looking at the levels of redox metals and corresponding strand breaks in DNA in two brain regions of the aging brain. The biological significance of these findings with relevance to mental health will be discussed.

Introduction

The failure in normal healthy aging leads to mental disorders in aged population.[sup] [1] Bipolar disorder (BD) is a major geriatric mental health problem. It affects about 1% of the population and causes severe neuropsychological impairments and has been implicated in functional impairment.[sup] [2] What we mean by normal and healthy aging and for that matter what are the triggering risk factors for geriatric mental health problems are still puzzling. To understand this better, we need to explore the biology of aging properly. Both structural, chemical, functional brain imaging using magnetic resonance imaging and postmortem studies have demonstrated volume loss in brain in subjects with BD and also with aging.[sup] [3],[4],[5],[6] Recent postmortem studies in BD have demonstrated reductions in number and density of nerve cells, as well as changes in cell body size and shape of neurons and glia, implicating specific cell pathology in the mood disorders and control aged brains.[sup] [4]

These studies give an insight into the central role played by neuronal cell death in the pathology of psychiatric disorders and is absent in normal healthy aging. The major risk factors implicated in age related disorders, is the elevation in oxidative stress and failure in antioxidant mechanisms.[sup] [7],[8],[9],[10],[11],[12] The oxidative stress phenomenon leads to DNA instability and gene expression failure in normal aging. Does the failure in repair mechanism lead to neuropsychiatric problems? The data base on this aspect is limited. A dysregulation in apoptotic mechanism is believed to play a role in a variety of neuropsychiatric disorders.[sup] [13],[14],[15],[16],[17],[18],[19] Further, DNA fragmentations have been well shown to be associated with neurodegenerative disorders like Parkinson disease (PD).[sup] [20],[21],[22],[23] The current study aims to assess the genomic integrity in terms of DNA fragmentation and its relation to the levels of redox active metals in frontal cortex and hippocampal brain regions of different age groups and to ascertain whether altered genome integrity plays a role in geriatric psychiatric disorders. …

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