Metabolic Pathways in Neurodegenerative Disorders

Neurodegenerative disorders are increasingly recognised as diseases of impaired cellular bioenergetics. In healthy neurons, glucose uptake, glycolysis and oxidative phosphorylation co-ordinate with the tricarboxylic acid cycle to generate adenosine triphosphate and maintain redox balance. In Alzheimer’s, Parkinson’s and related tauopathies, mitochondrial dysfunction, declines in nicotinamide adenine dinucleotide availability and disrupted reactive oxygen species buffering contribute to synaptic failure and axonal degeneration. Energy-sensing kinases, notably AMP-activated protein kinase, adjust metabolic fluxes and can influence pathogenic protein phosphorylation. Glial cells further modulate neuronal fuel supply and antioxidant defences, while long-range axons prove especially vulnerable to local bioenergetic stress. A clearer understanding of these intersecting pathways offers routes to rational therapeutic interventions aimed at restoring metabolic homeostasis and slowing neurodegenerative progression.

Research from Nature Portfolio

Seminal work on late-onset Alzheimer’s disease fibroblasts has revealed an inherent shift from mitochondrial respiration to glycolysis, coupled with impaired mitochondrial membrane potential and altered citric acid cycle activity. These cells exhibit a disease‐specific failure to upregulate glucose uptake despite increased glycolytic flux, implicating nicotinamide adenine dinucleotide metabolism as a critical vulnerability. A foundational investigation of AMP-activated protein kinase demonstrated its direct regulation of tau phosphorylation in neuronal models. Activation of this energy sensor increased tau hyperphosphorylation at multiple epitopes, whereas genetic or pharmacological inhibition attenuated tau pathology in vivo, establishing AMPK as a key modulator of microtubule stability and neurofibrillary tangle formation.

Metabolic Pathways in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in metabolic pathways in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Bioenergetics: The study of how cells convert nutrients into energy and maintain redox balance.

Glycolysis: The cytosolic pathway that breaks down glucose into pyruvate, yielding ATP and NADH.

Oxidative phosphorylation: Mitochondrial generation of ATP through electron transport and chemiosmosis.

Tricarboxylic acid cycle: A mitochondrial sequence of enzyme-catalysed reactions that oxidise acetyl-CoA.

Nicotinamide adenine dinucleotide (NAD+): A key redox cofactor essential for metabolic reactions and mitochondrial function.

AMP-activated protein kinase (AMPK): A cellular energy sensor that adjusts metabolic pathways in response to ATP depletion.

References

1. Axonal energy metabolism, and the effects in aging and neurodegenerative diseases. Molecular Neurodegeneration (2023).
2. Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles. Scientific Reports (2017).
3. AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. Scientific Reports (2016).
4. Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease. Frontiers in Neuroscience (2020).