Unbalanced Wnt signalling in AD: a DNA methylation effect

Project Information

eWAD

Grant agreement ID: 749209

DOI

10.3030/749209

Project closed

EC signature date 20 February 2017

Start date 1 March 2017

End date 28 February 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 183 454,80

EU contribution

€ 183 454,80

Coordinated by

UNIVERSITY COLLEGE LONDON
United Kingdom

Periodic Reporting for period 1 - eWAD (Unbalanced Wnt signalling in AD: a DNA methylation effect)

Reporting period: 2017-03-01 to 2019-02-28

Summary of the context and overall objectives of the project

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that accounts for two thirds of all dementia cases. AD is characterized by progressive cognitive impairment, memory loss and difficulties in daily tasks. At the microscopic level the AD brain is characterized by the accumulation of two proteins in particular: Amyloid-β (Aβ), which forms plaques outside the cells, and Tau protein, which forms fibrillary tangles inside the cells. The accumulation of these two molecules leads to neuronal loss at late stages of the disease. During early stages of AD, the brain suffers a decrease in the number of synapses – connections between neurons that transmit information, which correlates better with the cognitive impairment presented by the patients. Also implicated in the progression of AD is the Wnt signalling cascade, which normally contributes to the maintenance of synapses and function of neurons, but exactly how this pathway is affected in AD has been only partially described (Figure1).
Better understanding of how AD progresses at the molecular and cellular level, especially with regard to synapse degeneration, is extremely important for finding new therapeutic targets. Thus, projects like ours are important for society as they describe fine mechanisms affected by disease, which in the future could lead to more applied or translational research. To this end, our main objective is to identify the mechanisms that regulate the activity of the Wnt signalling cascade and its effect on synapse maintenance (Figure 1).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the fellowship, we have analysed approximately 40 different components of the Wnt signalling cascade in three different AD mouse models and in human AD samples. Our results point to a general deregulation of this signalling cascade and we hypothesised that a coordinated regulatory mechanism could be responsible for the changes we observed. In particular we focussed our investigation on epigenetic control. The Greek prefix epi-, meaning “on top of” or “above”, is used here to indicate regulatory factors that function in addition to the instructions encoded in DNA, the genes. For example, the expression of genes can be modified by altering the accessibility of regions of DNA, in addition to changes in the genetic code directly (Figure 2). Our results suggest that a particular epigenetic modification could be responsible for the changes in expression we observe for the components of the Wnt signalling cascade. We are now studying a range of targets and their effect on gene expression, with the hope of rescuing the Wnt signalling cascade and preventing synapse loss and memory deficits in AD models.
This fellowship has produced two manuscripts: a review article on Wnt signalling in the ageing brain and AD and a technical manuscript describing a novel approach for analysing gene expression in human brain samples. We will continue to exploit our results by publishing articles in high impact journals and we will continue the dissemination of our work at national and international scientific conferences. If any of our results can be patented, we will seek appropriate advice form UCL patent office.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our project is leading to discover possible mechanisms that cause synapse degeneration in AD. We expect to identify a particular protein responsible for the general deregulation of the Wnt signalling cascade. Thus, our work has the potential to impact society in the future by identifying new therapeutic targets for the treatment of Alzheimer’s disease.

Epigenetic (Figure 2)

Wnt Signalling (Figure 1)