Understanding the role that genes play in Alzheimer's disease tau tangles

Lead Investigator: Dr Richard Wade-Martins

Institution: University of Oxford

Grant type: PhD

Duration: 36 months

Amount: £75,000

Start date: October 2012

End date: September 2015

Scientific Title: Molecular mechanisms underlying haplotype-specific regulation of expression at the MAPT locus.

What was the project, and what did the researchers do?

A person's risk of developing dementia or other age-related brain diseases can be affected by their genetics. For example, levels of abnormal tau protein in the brain, a hallmark of some types of dementia and other brain disorders, is thought to be linked to particular sets of genes. The mechanism that causes this association is not well understood. This PhD project looked in close detail at the interaction between different versions of genes and levels of abnormal tau. 

Many different genes and processes are involved in making tau protein. This means that many different forms of the tau protein exist. Some of these forms can clump together in tangles, which are thought to cause damage to brain cells and play a role in dementia progression. There is some evidence to suggest that other forms of tau can protect the brain from damage caused by abnormal tau protein tangles.

Very small variations in different people's genes can affect how much of each form of tau is made. This means that some people might be more susceptible than others to abnormal tau tangles and dementia or other brain disorders.

It is not currently known what small variations exactly play a role in altering levels of tau forms or how the variations interact with the protein making processes in the cell to cause this alteration. The PhD student carried out lots of experiments to try to answer these questions.

The team measured levels of different forms of tau in brain cells in the lab and then analysed the cells' DNA, looking for which variations exactly were associated with different levels of tau protein. 

What were the key results, and how will this help in the fight against dementia? 

The student found a particular gene variation associated with a form of tau that may protect against the formation of the harmful tangles. They also uncovered differences in the way the cell processes the variations.

This research helps the fight against dementia in two ways. Firstly, it points to some specific variations that might affect tau levels. This finding could be useful for further research into the genetics behind dementia, and could inform new treatment and diagnostic methods. Secondly, the researchers used a new technique in this project. They looked at several genes found close together, rather than just one gene. This technique allowed them to look at complex interactions better, indicating that it could be an important method for similar research to use. 

What happened next? Future work and additional grants

The PhD student plans to continue researching this area as a post-doctoral researcher.

How were people told about the results? Conferences and publications

Publications

Mang Ching Lai, Anne-Laure Bechy, Franziska Denk, Maria Gavriliouk, Brent J. Ryan, Richard Wade-Martins, Tara M. Caffrey (2016) A common intronic single nucleotide polymorphism associated with neurodegenerative disease regulates H1/H2 haplotype-specific MAPT exon 3 expression (Submitted)

Conferences and presentations

Alzheimer's Society's Research Talk, Chippenham, March 2015

The 12th international conference on Alzheimer's and Parkinson's diseases and related neurological disorder (AD/PDTM 2015)

Posters

Molecular mechanisms underlying haplotype-specific regulation of gene expression at the microtubule associated protein tau locus