Imagine an orchestra playing a complex and beautiful symphony. And now imagine there are 25,000 musicians in the orchestra. This is one way to picture how our genes work together to control the function of our brains. Mammals have around 25,000 genes, and so this takes some coordination. In people with Alzheimer’s, and other causes of dementia, there are clear changes in gene activity. For example, the activity of genes involved in communication between nerve cells decrease as cells die.
In brain tissue generously donated by those with dementia, we can get a snap-shot of gene activity at the very final stages of the disease, but no idea of the ongoing changes that occur as the disease progresses. For example if you hear the final few notes of the symphony you have little idea of how the piece started and developed.
Measuring gene activity
The idea behind our research was to measure the activity of most genes in mice with different types of dementia, before they had any signs of disease and then as the disease progressed, allowing us to understand how the fine tuning of these genes changes through the different stages of the disease. We also wanted to make all of the data publically available so that any dementia researcher around the world could view the results, and any researchers interested in specific genes could quickly see if their area of expertise could be applied to dementia. Bringing different scientific communities together to tackle dementia, using their specialist and diverse skills, is key to accelerating progress against diseases such as Alzheimer’s. Our data are freely available at: www.mouseac.org.
To measure gene activity we used ‘microarrays’. Microarrays contain short sticky fragments of DNA attached to a microscope slide, and each DNA fragment sticks specifically to the biological molecules produced when a gene is active. The amount of the gene ‘product’ attached to each of the individual DNA fragments can be measured to tell us the activity of each gene. Each microarray slide contains around 25,000 DNA fragments, at least one for each gene.
Early signs in nerve cells
The mice we used with different types of dementia developed either amyloid plaques around nerve cells or tau tangles inside of cells. You can think of amyloid and tangles as cellular junk that can’t be completely recycled. These two features are the key hallmarks of Alzheimer’s and by studying the gene activity in mice with only one or the other we can tease apart their effects on the brain. Our studies provide several new insights into the disease process. Firstly, we identified a number of genes that show altered activity before any plaques or tangles had developed. These early acting genes were mainly involved in nerve cell communication, and may allow us to understand how nerve cell activity changes at the very earliest stages of the disease.
Other genes, involved in immune responses, were activated as the amyloid plaques developed, but didn’t respond to tau tangles. It is not clear what these immune response genes are doing; it may be that the brain immune cells are trying to remove the accumulating amyloid plaques, but it is also possible that immune cell activation causes further damage to the brain.
Finally, we saw that mice with tangles at the very final stages of the disease show decreased activity of genes involved in nerve cell function. We think tau tangles are killing nerve cells. Overall, our findings suggest that nerve cell activity changes before plaques are formed, but as plaques appear the immune cells try to combat the amyloid. Eventually, if the rise in amyloid is not halted, tangles develop and cause the death of nerve cells.
We can extend our findings further using modern computer science. By using complex computer processes, we can group together genes into ensembles that show similar changes in activity – just as with our orchestra where members of the brass section play together. After creating these ensembles, we can understand why these collections of genes change together. If we compare the activity of pairs of genes across different mice at different ages we can work out the extent to which different genes ‘talk to each other’ and which genes act as ‘hub’ genes – leaders of each section of the orchestra. Using these new computer science approaches, we can begin to identify new genes and new gene networks that we can target to understand the progression of dementia, create better ways of studying the disease in mice, and detect the disease at an earlier stage. Studying gene activity in this way may also allow us to help develop effective therapies. The funding from Alzheimer’s Research UK helps us apply these cutting edge research methods to dementia.
The original research article is available at http://www.cell.com/cell-reports/abstract/S2211-1247(14)01094-8