Selective Neuronal Vulnerability to Oxidative Stress in the Brain

By Elias K. Michaelis. Front. Ag. Neurosci., 2010

985 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/b940dca2ff2b5d90f50b859221451da4f8ffd70c

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In Cellular and Molecular Neuroscience

1. S. Gandhi
2. A. Abramov
3. Chunyan Guo
4. Xueping Chen
5. S. Salim

In Neurology

1. S. Gandhi
2. D. Bailey
3. A. Abramov
4. Maria Luisa Fiorello
5. S. Salim
6. J. Cobley
7. M. Conrad

In Physiology

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2. D. Bailey
3. A. Abramov
4. Chunyan Guo
5. J. Kong
6. Xueping Chen
7. I. Peluso
8. Maria Luisa Fiorello

Citations in the corpus

• Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration (2017, result): “The finding that neurodegeneration in Gpx4BIKO mice occurred in hippocampus is also consistent with other reports showing the increased sensitivity of hippocampal neurons, particularly the pyramidal neurons in the CA1 layer, to oxidative stress [24].”
• The Role of Oxidative Stress in Neurodegenerative Diseases (2015, background): “Third, the high levels of polyunsaturated fatty acids are found in the brain cell membranes and react as substrates for lipid peroxidation [68].”
• 13 reasons why the brain is susceptible to oxidative stress (2018, background): “Necrotic cell death amplifies excitotoxicity by elevating extracellular [glutamate] [78].”
• Oxidative Stress and the Central Nervous System (2017, positive): “tible to oxidative stress in some studies (Wang and Michaelis, 2010), and consequently are purported to be the first to undergo functional decline.”
• Mechanism of Oxidative Stress in Neurodegeneration (2012, background): “For example, in the hippocampus CA1 neurons generate higher levels of superoxide anion than CA3 neurons and exhibit higher levels of expression of both antioxidant and ROS-producing genes [70].”
• Oxidative stress in neurodegenerative diseases (2012, background): “While many brain neurons can cope with a rise in oxidative stress, there are selected populations of neurons that are vulnerable to increase oxidative stress, this phenomenon in neurodegenerative conditions is called selective neuronal vulnerability [25] .”
• Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases (2020, background): “High ATP demand, in combination with dysfunctional mitochondria, make these neuron groups more sensitive to degeneration (Wang and Michaelis, 2010).”