Calcium Dysregulation in Neurodegenerative Diseases

Calcium ions act as ubiquitous second messengers in neuronal function, governing processes from synaptic transmission to gene expression. In health, precise control of intracellular Ca2+ concentration underpins memory formation, synaptic plasticity and metabolic coupling. In neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, this homeostatic balance is disrupted at multiple levels. Aberrant Ca2+ influx through plasma-membrane channels, excessive release from endoplasmic reticulum stores and impaired mitochondrial handling converge to produce cytosolic overload. Such dysregulation precipitates mitochondrial dysfunction, oxidative stress and activation of cell-death pathways. Pathogenic proteins including amyloid-β oligomers, mutant presenilins and misfolded tau directly perturb ER-Ca2+ release channels and mitochondrial transporters, amplifying calcium-induced calcium release and compromising neuronal survival. Insights into these interlinked pathways have spurred the identification of calcium flux modulators as candidates for neuroprotective intervention, underscoring the global significance of restoring calcium homeostasis in ageing brains.

Research from Nature Portfolio

Recent examinations of mitochondrial calcium dynamics in Alzheimer’s models have illuminated how plaque-associated amyloid-β elevates intramitochondrial Ca2+, triggering neuronal death. Intravital imaging using targeted Ca2+ indicators has shown that inhibition of the mitochondrial calcium uniporter can prevent this overload. Complementary studies reveal that deficiency of the mitochondrial Na+/Ca2+ exchanger exacerbates disease progression in murine Alzheimer’s models, accelerating amyloidosis, tau pathology and memory decline. Genetic restoration of exchanger function restores Ca2+ efflux, reduces oxidative stress and ameliorates cognitive deficits, highlighting both uniporter and exchanger as therapeutic targets to rebalance mitochondrial Ca2+ in neurodegeneration.

Calcium Dysregulation in Neurodegenerative Diseases publication trend

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

Technical terms

Calcium homeostasis: Regulation of intracellular Ca2+ levels to support signalling and prevent toxicity.

Endoplasmic reticulum (ER): Intracellular organelle that stores Ca2+ and releases it via IP3 and ryanodine receptors.

Mitochondrial calcium uniporter (MCU): Channel complex allowing Ca2+ entry into mitochondria, affecting energy production and apoptosis.

Mitochondrial Na+/Ca2+ exchanger (NCLX): Transporter mediating Ca2+ extrusion from mitochondria to maintain ionic equilibrium.

Ryanodine receptors (RyR): ER membrane channels that release Ca2+ in response to cytosolic Ca2+, integral to calcium-induced calcium release.

Calcium-induced calcium release (CICR): Amplification mechanism where Ca2+ entry triggers further release from intracellular stores.

References

1. Hyperoside alleviates toxicity of β-amyloid via endoplasmic reticulum-mitochondrial calcium signal transduction cascade in APP/PS1 double transgenic Alzheimer's disease mice. Redox Biology (2023).
2. Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer’s disease. Brain (2024).
3. Amyloid β-Oligomers Inhibit the Nuclear Ca2+ Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons. Antioxidants (2023).
4. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease. Nature Communications (2020).
5. Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nature Communications (2019).