Summary: Regular physical exercise changes how iron is stored and transported in both the brain and skeletal muscles, and it lowers cortical hepcidin levels. These results clarify one mechanism by which exercise may offer protection in Alzheimer’s disease.
Source: University of Eastern Finland
New experimental evidence shows that sustained physical activity reshapes iron metabolism in the brain and in skeletal muscle, and the findings shed light on why exercise can be beneficial in Alzheimer’s disease (AD).
The research appears in a special issue of the International Journal of Molecular Sciences focused on Redox Active Metals in Neurodegenerative Diseases and their therapeutic implications.
Abnormal iron handling and iron accumulation in the brain are linked to aging and to AD, but the precise mechanisms driving these changes are not fully understood. Hepcidin, the central regulator of systemic iron, is influenced by both iron levels and inflammatory signals. In particular, the cytokine interleukin-6 (IL-6)—which also plays a role in communication between muscle and brain—is known to trigger hepcidin production in neural tissue.
While regular exercise is already recognized for improving whole-body iron balance and reducing inflammation, its specific effects on brain iron homeostasis and how those effects relate to AD have not been clearly defined.
To explore this, researchers used both wild-type mice and the 5xFAD transgenic mouse model of Alzheimer’s disease. During a six-month period, half of the animals in each group had continuous access to a running wheel, allowing voluntary long-term exercise. After the intervention, the team measured total iron content and assessed levels of proteins that control iron handling in brain tissue and in skeletal muscle.
The investigators specifically examined whether iron participates in the communication between the brain and peripheral tissues during regular exercise, and how exercise alters iron-related signaling molecules in these compartments.
Overall, the study found that long-term voluntary running led to a redistribution of iron: exercise altered iron metabolism and trafficking in the brain while increasing iron content in skeletal muscle. Importantly, this work is the first to report that regular physical exercise reduces levels of cortical hepcidin, the peptide hormone that finely tunes iron availability in neural tissue.
The authors observed that reductions in cortical hepcidin occurred alongside decreased IL-6 levels in both cortex and plasma, suggesting that the IL-6 signaling pathway may link physical activity with lowered hepcidin expression in the brain. The researchers propose that exercise may act through an IL-6/STAT3/JAK1 cascade to downregulate central hepcidin and thereby adjust brain iron handling.
These findings were consistent in both wild-type and 5xFAD mice, indicating that the exercise-induced modulation of iron homeostasis occurs regardless of AD pathology in this model. By altering iron distribution and reducing inflammatory signaling, sustained physical activity may help prevent or mitigate pathological iron accumulation that contributes to neurodegeneration.
Understanding how lifestyle factors like exercise influence brain iron regulation offers a plausible biological explanation for some of the cognitive benefits associated with regular physical activity. The results add to a growing body of evidence that exercise supports brain health by multiple mechanisms, including metabolic, inflammatory, and now iron-regulatory pathways.
This work was conducted in the Neurobiology of Disease laboratory led by Associate Professor Katja Kanninen at the University of Eastern Finland.
Funding: The study received support from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cultural Foundation, and the University of Eastern Finland.
About this exercise and Alzheimer’s disease research news
Author: Ulla Kaltiala ([email protected])
Source: University of Eastern Finland
Contact: Ulla Kaltiala – University of Eastern Finland
Image: The image is in the public domain
Original Research: Open access. “Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease” by Katja Kanninen et al., International Journal of Molecular Sciences
Abstract
Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease
Disrupted iron metabolism in the brain is a recognized feature of aging and Alzheimer’s disease, which is characterized clinically by progressive memory loss and cognitive decline.
Physical inactivity is a modifiable risk factor for dementia, and regular exercise is known to improve cognition and reduce AD-related pathology. However, the mechanisms that connect exercise with these protective effects are not fully resolved.
This study examined how long-term voluntary exercise affects iron homeostasis in both brain and peripheral muscle tissue in the 5xFAD mouse model of AD. Using inductively coupled plasma mass spectrometry and multiple biochemical assays, the research team measured total iron and quantified proteins that regulate iron handling in the cortex and skeletal muscle of sedentary and exercised animals.
Results showed that extended voluntary running prompted a redistribution of iron, altered iron metabolism and trafficking in the brain, and increased iron content in skeletal muscle. Exercise lowered cortical hepcidin levels and reduced IL-6 in cortex and plasma, supporting a model in which exercise reduces brain hepcidin possibly through the IL-6/STAT3/JAK1 signaling pathway.
These data indicate that regular physical exercise modulates iron homeostasis in both healthy and AD-model mice, offering a potential mechanistic link between exercise and reduced neurodegenerative risk.