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Exercise revealed as top theoretical Alzheimer’s treatment

Written by Lauren Robertson, Science Writer.

Want to know how to stave off the effects of Alzheimer’s disease (AD)? Get on your bike! (And we mean this quite literally).

A recent paper, published in Scientific Reports, has revealed that exercise is the top (theoretical) treatment for AD. The finding is the result of a large-scale gene expression analysis encompassing 22 AD datasets and confirms a plethora of other research suggesting regular exercise is the key to preventing neurodegeneration.

Gene expression at the large scale

There is no denying that AD is a complex disorder. Thousands of dysregulated genes across multiple brain regions make up a profile of disease that is very difficult to treat successfully. In fact, previous large-scale gene expression studies have highlighted more than 20,000 genes involved in the disorder.

To better understand which potential treatments might be successful against AD, Mason Hill and Stephanie Gammie from the University of Wisconsin-Madison analysed 22 large-scale AD gene expression datasets from publicly available human genomes. Using this data, they were able to create a portrait of gene expression for AD across multiple brain regions that could then be used to identify those treatments capable of reversing dysregulated gene expression patterns.

Their approached involved “signature matching” these expression profiles to potential drugs that can be re-purposed for treating AD. They found 3 genes that exhibited the most dysregulation – inositol trisphosphate kinase (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase (upregulated). These dysregulated genes covered multiple processes, from cell adhesion to central nervous system development.

Figure 1: Top connected genes in AD portrait. Genes with the highest levels of protein–protein interaction from the top 1000 dysregulated genes in AD portrait are plotted in Cystoscape. Interactions are highlighted by lines. AD upregulated genes are shown in red and AD downregulated genes are show in blue. Increased size of font for gene symbol reflects higher number of connections between genes. GAPDH and ACTB were the two genes with the most connections. Also plotted are a subset of AD portrait genes also identified in a recent GWAS analysis of AD (shown with an asterisk).

Healthy body, healthy mind

They then used this AD gene portrait to evaluate the impact of certain treatments on AD. Out of more than 250 treatments, three datasets for exercise (or activity) were highlighted as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns.

The top two treatments reversed 409 and 344 AD genes respectively. Overall, exercise appeared to reverse the expression of hundreds of AD genes involved in the cytoskeleton, blood vessel development, mitochondria, and interferons. The effect on blood vessel development may be of particular interest to researchers as decreased blood flow is associated with AD, while exercise can help elevate brain blood flow.

Besides the wider-scale impacts of exercise on the brain, the researchers also found that exercise came up trumps in region-specific analyses of AD datasets, adding more clout to their results. Intriguingly, the anti-depressant medicine Fluoxetine scored well in the analysis, and a combination of this drug and regular exercise could reverse up to 549 AD genes. Curcumin was also highlighted as a positive treatment for AD.

The specific approach used in this study is more likely to identify global patterns of gene expression, rather than alterations specific to a certain brain region. However, these findings line up well with other studies looking at specific brain regions and could provide a platform for the evaluation of more treatments that have the potential to reverse some of the devastating impacts of AD.

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