Selective neuronal vulnerability to oxidative stress in the brain - PubMed (original) (raw)

Selective neuronal vulnerability to oxidative stress in the brain

Xinkun Wang et al. Front Aging Neurosci. 2010.

Abstract

Oxidative stress (OS), caused by the imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS), plays an important role in brain aging, neurodegenerative diseases, and other related adverse conditions, such as ischemia. While ROS/RNS serve as signaling molecules at physiological levels, an excessive amount of these molecules leads to oxidative modification and, therefore, dysfunction of proteins, nucleic acids, and lipids. The response of neurons to this pervasive stress, however, is not uniform in the brain. While many brain neurons can cope with a rise in OS, there are select populations of neurons in the brain that are vulnerable. Because of their selective vulnerability, these neurons are usually the first to exhibit functional decline and cell death during normal aging, or in age-associated neurodegenerative diseases, such as Alzheimer's disease. Understanding the molecular and cellular mechanisms of selective neuronal vulnerability (SNV) to OS is important in the development of future intervention approaches to protect such vulnerable neurons from the stresses of the aging process and the pathological states that lead to neurodegeneration. In this review, the currently known molecular and cellular factors that contribute to SNV to OS are summarized. Included among the major underlying factors are high intrinsic OS, high demand for ROS/RNS-based signaling, low ATP production, mitochondrial dysfunction, and high inflammatory response in vulnerable neurons. The contribution to the selective vulnerability of neurons to OS by other intrinsic or extrinsic factors, such as deficient DNA damage repair, low calcium-buffering capacity, and glutamate excitotoxicity, are also discussed.

Keywords: aging; energy metabolism; glia; mitochondria; neurodegeneration; oxidative stress; selective neuronal vulnerability; signaling.

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Figures

Figure 1

Figure 1

Molecular and cellular factors that contribute to the selective vulnerability of neurons to oxidative stress. ROS/RNS can serve as signaling molecules while they cause damages to bio-molecules at increased levels. Neurons in different parts of the brain have differential needs for ROS/RNS as signaling molecules, with some neurons (such as those in the hippocampal CA1 region) having higher demand than others. However, due to the duality of ROS/RNS, the high demand for these highly reactive species may lead to intrinsically high OS in some neurons, which can make them selectively vulnerable when facing increased stress. Vulnerable neurons are also characterized by low ATP production and mitochondrial dysfunction, possibly because of the high OS state in these neurons, and other factors such as calcium dysregulation. Low ATP production can affect DNA repair, which, when combined with high DNA oxidation, can cause change of genomic activity and decreased metabolic activity in mitochondria. Functional genomics studies also suggest existence of chronic inflammatory response in vulnerable neurons, which can further elevate OS within them. Calcium dysregulation and glutamate hyperactivity are closely connected to OS generation and underlie many adverse conditions that are characterized by SNV. There is emerging evidence that directly connects these factors, such as low calcium-buffering capacity and glutamate-mediated selective neurodegeneration, to the selective vulnerability of neurons. The colored arrows that link these mechanistic factors in the figure denote direct relationships between them. In addition, vulnerable neurons tend to be large in size, with long projecting axons to their targets.

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