Thiamine Metabolism and Oxidative Stress in Neurodegenerative Diseases

Thiamine, or vitamin B1, is converted within cells to thiamine diphosphate (ThDP), a pivotal coenzyme for pyruvate dehydrogenase and the α-ketoglutarate dehydrogenase complex (KGDHC) in the tricarboxylic acid (TCA) cycle. Adequate ThDP levels are essential for efficient energy production in neurons and glia, while deficiency impairs mitochondrial function, reduces ATP synthesis and precipitates accumulation of reactive oxygen species (ROS). Oxidative stress, arising when ROS generation overwhelms antioxidant defences, contributes directly to lipid peroxidation, protein oxidation and mitochondrial DNA damage. In neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease, perturbations in thiamine metabolism and consequent enzyme inhibition exacerbate oxidative injury, disrupt neurotransmitter synthesis and promote aggregation of pathological proteins. Metabolism-linked post-translational modifications—such as succinylation—can bridge energy deficits with hallmark pathological processes, including amyloid-β plaque formation and tau tangles. Moreover, cross-talk between neurons and microglia under thiamine-restricted states influences inflammatory signalling and oxidative bursts. Together, these mechanisms underscore the global significance of maintaining thiamine-dependent bioenergetics and redox balance as a therapeutic strategy to slow or prevent neurodegenerative progression.

Research from Nature Portfolio

Recent studies have revealed that the pattern of protein succinylation shifts markedly in Alzheimer’s disease, linking metabolic dysregulation with core pathological events. Analyses of human brain tissue demonstrated a decline in succinylation of multiple mitochondrial enzymes, while succinylation increased at critical lysine residues on amyloid precursor protein (APP) and microtubule-associated tau. In vitro experiments showed that succinylation of APP alters its proteolytic processing to favour amyloid-β accumulation, and succinylated tau displays enhanced aggregation and impaired microtubule assembly. Transgenic mouse models corroborated these findings, with elevated succinylation correlating with both soluble and insoluble APP derivatives and tau species. These observations provide a metabolism-linked molecular mechanism connecting TCA cycle perturbations to protein misfolding and cognitive decline.

Thiamine Metabolism and Oxidative Stress in Neurodegenerative Diseases publication trend

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

Technical terms

Thiamine diphosphate (ThDP): The active coenzyme form of vitamin B1 that facilitates key decarboxylation reactions in energy metabolism.

α-Ketoglutarate dehydrogenase complex (KGDHC): A rate-limiting enzyme of the tricarboxylic acid cycle that catalyses conversion of α-ketoglutarate to succinyl-CoA.

Oxidative stress: A condition arising from an imbalance between the production of reactive oxygen species and the capacity of antioxidant defences.

Reactive oxygen species (ROS): Highly reactive molecules derived from oxygen, including free radicals, that can damage proteins, lipids and nucleic acids.

Succinylation: A metabolic-linked post-translational modification involving attachment of a succinyl group to lysine residues, altering protein structure and function.

Tricarboxylic acid cycle (TCA cycle): A series of mitochondrial reactions oxidising acetyl-CoA to generate NADH and FADH₂, which drive ATP synthesis.

References

1. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease. Nature Communications (2022).
2. Effects of Marginal Zn Excess and Thiamine Deficiency on Microglial N9 Cell Metabolism and Their Interactions with Septal SN56 Cholinergic Cells. International Journal of Molecular Sciences (2023).
3. Parapyruvate Induces Neurodegeneration in C57BL/6JNarl Mice via Inhibition of the α‑Ketoglutarate Dehydrogenase Complex. ACS Omega (2024).
4. Systemic alterations of tricarboxylic acid cycle enzymes in Alzheimer’s disease. Frontiers in Neuroscience (2023).