Gene linked to exercise could be a target for Alzheimer's treatment

Exercise can induce protective gene activity in the brain cells of Alzheimer's model mice, uncovering new understanding of disease mechanisms.

By comparing Alzheimer's model mice either kept sedentary or given access to a free running wheel for 60 days, researchers showed that exercise triggered better cognitive performance. In parallel, exercise restored cell-type specific gene activity dysregulated by the neurodegenerative disease. The researchers identified changes in gene activity in microglia, Alzheimer's disease-associated brain cells, as well as astrocytes and oligodendrocytes, important for neuron and blood vessel protection and developing immature neurons.

'While we've long known that exercise helps protect the brain, we didn't fully understand which cells were responsible or how it worked at a molecular level,' said co-senior author Dr Christiane Wrann, affiliated with both the Cardiovascular Research Centre and Centre for Brain Health of Massachusetts General Hospital and Harvard Medical School in Boston.

Published in Nature Neuroscience, the study used single-nucleus RNA sequencing (snRNA-seq) to examine gene activity across thousands of individual cells extracted from hippocampus tissue, a brain region responsible for learning and memory and affected early in Alzheimer's disease.

'Now, we have a detailed map of how exercise impacts each major cell type in the memory centre of the brain in Alzheimer’s disease,' Dr Wrann continued.

They also assessed exercised healthy mice, enabling the researchers to pinpoint genes relevant to exercise in Alzheimer's disease specifically, and then validated these genes in a human Alzheimer's snRNA-seq dataset.

'This work not only sheds light on how exercise benefits the brain but also uncovers potential cell-specific targets for future Alzheimer's therapies,' said other co-senior author Dr Nathan Tucker at Upstate Medical University of State University of New York.

Across cell types, around half of dysregulated genes could be restored by exercise, especially in cells with reduced abundance in the Alzheimer's model mice. In some cases, restored gene activity returned to levels seen in the healthy mice. This included the Atpif1 gene, which through a separate experiment the researchers showed was important for regulating hippocampal adult neurogenesis (new neuron formation).

‘That we were able to modulate newborn neurons using our new target genes set underscores the promise our study,’ said lead author Dr Joana Da Rocha, postdoctoral fellow at Massachusetts General Hospital and Harvard Medical School.

Previous work in the journal Science showed that exercise-triggered neurogenesis led to improvements in cognition, but the genetic mechanism was not understood.

However, while providing the first-of-its-kind dataset to explore disease mechanisms and environment-gene interactions, the authors also highlighted important limitations to their work. Their specific Alzheimer's model displayed amyloid but not tau pathology – a key hallmark of the disease – and only male mice were used, limiting generalisation of the findings. Furthermore, exercise leads to different feeding patterns and metabolism, so the precise causality between exercise and the findings cannot yet be determined.