What is neurodegeneration?

Neurodegeneration refers to the progressive loss of structure or function of neurons, the cells that make up the nervous system, including the brain and spinal cord. This process is typically associated with the gradual decline in cognitive function, motor function, or both, depending on the areas of the nervous system affected.


Neurodegeneration can occur in various neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), among others. While the specific mechanisms underlying neurodegeneration may vary between different diseases, common features include:


  • Accumulation of Abnormal Proteins: In many neurodegenerative disorders, abnormal proteins accumulate within neurons or in the surrounding tissue. Examples include amyloid-beta and tau in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, huntingtin in Huntington’s disease, and misfolded proteins in ALS. The accumulation of these proteins can disrupt normal cellular function, leading to neuronal dysfunction and death.


  • Oxidative Stress: Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the ability of cells to detoxify them or repair the resulting damage. Neurons are particularly vulnerable to oxidative stress due to their high metabolic activity and relatively low levels of antioxidant defenses. Oxidative damage to proteins, lipids, and DNA can contribute to neuronal dysfunction and death in neurodegenerative diseases.


  • Mitochondrial Dysfunction: Mitochondria are the energy-producing organelles within cells and play a crucial role in maintaining neuronal function. Dysfunction of mitochondria, including impaired energy production, oxidative stress, and release of pro-apoptotic factors, has been implicated in neurodegeneration. Mitochondrial dysfunction can lead to neuronal cell death and contribute to the progression of neurodegenerative diseases.


  • Inflammation: Inflammation is a common feature of many neurodegenerative diseases and can contribute to neuronal injury and death. Activated microglia, the resident immune cells of the central nervous system, release pro-inflammatory cytokines, chemokines, and reactive oxygen species, which can exacerbate neuronal damage and contribute to neurodegeneration.


  • Excitotoxicity: Excitotoxicity refers to the toxic effects of excessive glutamate signaling on neurons. Excessive glutamate release can lead to overactivation of glutamate receptors, particularly NMDA receptors, resulting in calcium influx, mitochondrial dysfunction, and ultimately, neuronal death. Excitotoxicity has been implicated in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.


Overall, neurodegeneration involves a complex interplay of genetic, environmental, and cellular factors that contribute to the progressive loss of neuronal structure and function.


What is the relationship between neurodegeneration and oxidative stress?

The relationship between neurodegeneration and oxidative stress is intricate and multifaceted. Oxidative stress is recognized as a significant contributor to the pathogenesis and progression of various neurodegenerative diseases. Several factors contribute to this relationship:


  • Accumulation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS): In neurodegenerative diseases, there is often an imbalance between the production and elimination of ROS and RNS. ROS, such as superoxide radicals, hydroxyl radicals, and hydrogen peroxide, and RNS, such as nitric oxide, are highly reactive molecules that can damage cellular structures including lipids, proteins, and DNA. The accumulation of ROS and RNS leads to oxidative stress, contributing to neuronal dysfunction and death.


  • Mitochondrial Dysfunction: Mitochondria are major sources of ROS production within cells, and dysfunctional mitochondria are commonly observed in neurodegenerative diseases. Mitochondrial dysfunction can lead to increased ROS production, impaired energy metabolism, and release of pro-apoptotic factors, exacerbating oxidative stress and neuronal damage.


  • Accumulation of Oxidatively Modified Biomolecules: Oxidative stress leads to the oxidation of biomolecules such as lipids, proteins, and DNA within neurons. For example, lipid peroxidation can result in the generation of toxic byproducts that damage cell membranes and disrupt cellular function. Oxidative modification of proteins can impair their function and lead to aggregation, a hallmark of many neurodegenerative diseases. DNA damage induced by oxidative stress can lead to mutations and genomic instability, contributing to disease progression.


  • Inflammation: Neuroinflammation, characterized by the activation of microglia and release of pro-inflammatory cytokines and chemokines, is a common feature of neurodegenerative diseases. Inflammatory processes contribute to oxidative stress through the activation of NADPH oxidase and the release of ROS by activated immune cells. Chronic inflammation and oxidative stress form a vicious cycle, with each process exacerbating the other and leading to progressive neuronal damage.


  • Impaired Antioxidant Defenses: Antioxidant defenses play a crucial role in mitigating oxidative stress and protecting neurons from damage. However, in neurodegenerative diseases, there is often a decline in antioxidant capacity due to decreased expression or activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. This impaired antioxidant defense system further contributes to oxidative stress and neuronal vulnerability.


Overall, oxidative stress is intimately linked to neurodegeneration, contributing to neuronal dysfunction, cell death, and disease progression in various neurodegenerative diseases.