Investigating the interactions that cause tau to form tangles in Alzheimer's disease

Research project: Mechanisms underlying the tau protein-mediated effects of amyloid beta on synaptic plasticity

Lead Investigator: Dr Richard Wade-Martins
Institution: University of Oxford
Grant type: Project
Grant amount: £223, 092
Start date: October 2013
Completion date: December 2016

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

Alzheimer's disease results from the build-up of two proteins in the brain; toxic tau tangles inside of the cell and amyloid plaques outside of it. 

The most widely accepted explanation of the relationship between these two proteins is called the 'amyloid hypothesis.' It suggests that amyloid accumulation comes before the tau tangle formation. This build-up of the amyloid protein then triggers tau accumulation, which disrupts the functioning of brain cells and eventually leads to their death. 

Dr Wade-Martins previously showed that without the presence of tau, amyloid build up does not affect brain cell function. To continue this research, in this project the researchers again used mice that had their tau removed. They modified them further to produce the normal or an abnormal version of human tau. They studied the effects of amyloid and tau on the 'firing' of nerve cells in the brain, the effectiveness of which is thought to relate to the ability to form memories.

Secondly, they wanted to recreate the loss of tau in the mice in human brain cells that had been grown from skin stem cells in the lab. This technique involves taking a sample of human skin cells, altering them so that they become stem cells, and then developing them into brain cells. They used cutting-edge technology to 'delete' the gene that is responsible for the production of the tau protein and investigated the effects of this loss, and whether they are the same as seen in the mouse model.

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

The team were able to show that the human tau gene does interact with amyloid to impair nerve cells. They were also able to create mice that have a specific genetic modification in the tau gene that is known to be associated with a specific form of dementia. They showed in this model that the neurons are less able to send the signals that are necessary for memory formation and storage. 

The researchers have made great progress towards creating human brain cells that had been grown from skin stem cells in the lab that cannot produce the tau protein, however this work is still ongoing.

The researchers continue to seek to understand important aspects of the interaction between amyloid and tau proteins in Alzheimer's disease. This interaction is critical to brain cell dysfunction, memory impairment and cognitive decline. Understanding the interaction is an important and necessary step in the search for a treatment and cure for Alzheimer's disease.

What happened next? Future work and additional grants

The teams involved in this project are continuing their work with the mouse models of tau and amyloid. They are also striving forward to produce human brain cells with complete removal of the tau protein. This would prove invaluable in laboratory experiments and provide the researchers with a necessary tool for further investigation of the importance of tau in the underlying mechanisms of Alzheimer's disease.

How were people told about the results? Conferences and Publications

    Mariana Vargas-Caballero et al (2017) Wild-type, but not mutant N296H, human tau restores Abeta-mediated inhibition of LTP in Tau-/- mice. Frontiers in Neuroscience doi: 10.3389/fnins.2017.00201

    MRC DPUK Experimental Medicine Pilot Award (Principal Investigator Wade-Martins; Co-Investigators: Cader and Lovestone). Integration of clinical and cellular phenotypes in the UKDP Deep and Frequent Phenotype Cohort
    A new student, Ng Jeng Haur, will start work in the Wade-Martins laboratory in September 2017 on a DPhil funded by the Singapore A-STAR foundation. His work will follow up the work described here characterising a MAPT-/- line

Conference talks:     
    STEMBANCC meeting on Cortical Differentiation  July 2014 
    STEMBANCC meeting(s) on Genetic Editing  Dec 2014 
    Oxford StemBancc meetings July 2015 
    Oxford Stem Cell meeting August 2015 
    Oxford Gene Editing meeting May 2015

Poster presentations:     
    Oxford Neuroscience Symposium: June 2015.