Metal Homeostasis and Oxidative Stress in Neurodegenerative Diseases

Metal ions such as iron, copper, zinc, manganese and selenium play indispensable roles in neuronal physiology, serving as cofactors for enzymes involved in neurotransmitter synthesis, mitochondrial respiration and antioxidant defence. Precise regulation of uptake, distribution and storage—collectively termed metal homeostasis—ensures that redox-active metals catalyse essential reactions without generating excess reactive oxygen species. When this balance is lost, unbound metal ions participate in Fenton chemistry and redox cycling to produce hydroxyl radicals and superoxide, triggering oxidative stress. Chronic oxidative stress damages lipids, proteins and nucleic acids, disrupts mitochondrial and endoplasmic reticulum function, and promotes misfolding and aggregation of amyloid-β and hyperphosphorylated tau. These pathological hallmarks, together with neuroinflammation and synaptic dysfunction, drive the progressive neuronal loss characteristic of Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Evidence now points to a self-amplifying loop in which aberrant metal distribution exacerbates oxidative injury and protein aggregation, while accumulating aggregates further impair metal transport and antioxidant capacity.

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Metal Homeostasis and Oxidative Stress in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in metal homeostasis and oxidative stress in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Metal homeostasis: The cellular and systemic processes governing the uptake, distribution, storage and excretion of metal ions to maintain physiological concentrations.

Oxidative stress: A state in which the production of reactive oxygen species exceeds the capacity of antioxidant defences, resulting in cellular damage.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including superoxide anions and hydrogen peroxide, that can damage biomolecules.

Fenton reaction: A chemical reaction in which transition metals catalyse the conversion of hydrogen peroxide into highly reactive hydroxyl radicals.

Amyloid-β: A peptide derived from amyloid precursor protein that aggregates to form extracellular plaques in Alzheimer’s disease.

Tau hyperphosphorylation: The excessive addition of phosphate groups to tau protein, promoting its detachment from microtubules and aggregation into neurofibrillary tangles.

References

1. Metals linked with the most prevalent primary neurodegenerative dementias in the elderly: A narrative review. Environmental Research (2023).
2. Biometals in Alzheimer disease: emerging therapeutic and diagnostic potential of molybdenum and iodine. Journal of Translational Medicine (2023).
3. Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Translational Neurodegeneration (2020).
4. The essential elements of Alzheimer’s disease. Journal of Biological Chemistry (2020).