eWAD · Unbalanced Wnt signalling in AD: a DNA methylation effect
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-03-01 → 2019-02-28
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Unbalanced Wnt signalling in AD: a DNA methylation effect
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).
Data: CORDIS, © European Union
Project objective
Growing evidence suggests that unbalanced Wnt signalling contributes to early stages of Alzheimer´s Disease (AD). mRNA levels of the Wnt antagonist Dikkoff1 (Dkk1) are increased in AD brains and by Amyloid-ß (Aß) in vitro. Importantly, suppression of Dkk1 activity protects synapses from Aß. Genome-Wide Association Studies also provide evidence for deficient Wnt signalling in AD. The host laboratory has recently demonstrated that Dkk1 induced expression in the adult hippocampus leads to synapse loss and cognitive impairment; defects that can be restored by Wnt signalling reactivation. My preliminary results demonstrate that mRNA levels of several Wnt components (Wnts, their receptors and antagonists) are affected in a transgenic mouse model of familial AD, suggesting a general downregulation in Wnt signalling. These findings raise two main questions. Is aberrant expression of Wnt components an early event in AD? What mechanisms lead to aberrant Wnt component expression in AD? Given that Wnt signalling is crucial for synapse maintenance, and that my preliminary results suggest a coordinated downregulation of the Wnt pathway in AD, I will examine the role of DNA methylation at Wnt component genes in AD and how this affects synapse integrity. The potential role of DNA methylation is supported by: i) AD patients and mouse models exhibit global DNA hypomethylation and gene-specific DNA hypermethylation, ii) DNA methylation at promoters leads to gene repression, but intragenic methylation can enhance transcription, iii) Wnt components contain CpG islands at their promoters and/or intragenic regions, and iv) some Wnt components are regulated by DNA methylation in cancer. My work will define the role of epigenetic regulation of Wnt components under physiological conditions and determine the relevance of unbalanced Wnt signalling in AD. This research project could also identify new biomarkers and novel therapeutic targets for the treatment of early AD stages.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union