Investigating a way to clear tau tangles, a hallmark of Alzheimer's disease

Read about a research project we funded on the role of NUB1 in the clearance of tau aggregates in Alzheimer’s disease.

Lead Investigator: Dr Jaqueline van der Spuy

Institution: University College London

Grant type: PhD studentship

Duration: 3 years

Amount: £84,934

Why did we fund this project?

Comments from members of our Research Network:

'The impact of the relationship to Huntington's disease research findings to this study is clear and makes interesting and exciting the prospect of building on what has already been found.'

'That increased knowledge of NUB1 and its role applies to other diseases as well as Alzheimer's is good news.'

'The careful work already accomplished in this area at UCL gives a firm basis for the further exploration proposed here.'

What do we already know?

Alzheimer's disease is characterised by the accumulation of large clumps of proteins both inside and outside the nerve cells of the brain. These clumps interfere with the normal activity of these cells which consequently die.

The clumps on the outside of the cells are called plaques and are composed of a protein called amyloid-beta. The clumps formed inside cells are called neurofibrillary tangles and are composed of a protein called tau. New treatments that can either prevent these aggregates from forming or clear them from the nerve cells offer an exciting approach for tackling Alzheimer's disease.

Researchers have recently discovered that a protein called NUB1 reduces the accumulation of tau tangles in brain cells grown in the lab. Conversely, the accumulation of tau tangles is much worse following the loss of NUB1 from these cells. NUB1 may therefore protect cells against the damaging effects that occur as a result of the accumulation of tau tangles. Therefore, it is possible that NUB1 could serve as a target for therapeutic intervention in Alzheimer's disease. 

NUB1 has recently been implicated in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, Huntington's disease and Alzheimer's disease. It has therefore been proposed that NUB1 may serve as an entry point for therapeutic intervention in these diseases. In particular, there is mounting evidence that NUB1 is neuroprotective in several of these disorders, and that the increase of NUB1 could be a viable therapeutic strategy.

Preliminary findings from the research team's collaboration with other researchers suggest that the levels of the NUB1 gene are significantly increased early in the disease. Previously published research by this team also revealed that NUB1 targets abnormally modified, aggregation-prone tau but not the normal tau protein. Their published data also revealed that NUB1 can not only reduce the accumulation of aggregation-prone tau, but can also reduce the abnormal modification of tau. 

The researchers want to understand exactly how the tau tangles are cleared by NUB1 in cells and how it may prevent the abnormal tangle-prone form of tau from forming, so that this might be a viable target for therapeutic intervention in Alzheimer's disease.

A complete understanding of the functions of NUB1 described above will give us clues as to how these discoveries can be fully harnessed to develop new types of treatments for Alzheimer's disease that target NUB1.

What does this project involve?

In the first part of this study, the researchers want to find out how NUB1 changes in the brain over time as the symptoms of Alzheimer's disease worsen. In order to achieve this, they will use a mouse model of Alzheimer's disease.

The use of this model will enable them to conduct a long-term study that will track NUB1 in the brain at specific time points before, during and after the accumulation of abnormal protein and cognitive decline. The changes in NUB1 in the Alzheimer's disease mice will be compared to those in unaffected control mice of the same age to establish the changes in NUB1 that relate specifically to Alzheimer's disease. 

In the second part of the study, the researchers will use brain cells grown in the lab to investigate how NUB1 changes in Alzheimer's disease and to understand the implications of these changes in the progression of the disease. 

How will this benefit people with dementia?

In the struggle to find a cure or treatment for Alzheimer's disease, it is becoming clear that a concerted and coordinated effort targeting different aspects of the disease may be necessary. Ultimately, this study might improve the lives of people with dementia by not only increasing the current understanding of the disease, but also by opening up new avenues for treatment.

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