Principal Investigators

    Professor PC Salinas


    University College London

    Contact information of lead PI


    United Kingdom

    Title of project or programme

    Dkk1-Wnt signalling pathway in synapse degeneration: implication for early stages of Alzheimer's disease

    Source of funding information


    Total sum awarded (Euro)

    € 1,650,810

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Alzheimer's disease & other dementias


    Research Abstract

    Deficient Wnt signalling has been shown to contribute to Alzheimer’s disease (AD). Given the role of Wnts at the synapse, we propose that the secreted Wnt antagonist Dkk1, which is elevated by A-Beta, contributes to synapse failure in AD. Here we will examine the mechanisms responsible for synapse vulnerability and their impact to AD. We address the following specific aims: 1) To investigate the contribution of downstream components of the Wnt pathway in Dkk1-mediated synapse degeneration. Using a candidate approach, we will study key synaptic components of the Wnt pathway, the LRP6 receptor and the scaffold protein Dishevelled-1 (Dvl1). LRP6 is blocked by Dkk1 and has been linked to late onset AD in a genome wide association study. Moreover, Dvl1 is required for excitatory synapse formation and function. Here, we will evaluate the role of these proteins in synapse vulnerability. 2) To identify novel mechanisms contributing to Dkk1-mediated synapse vulnerability. Proteome and transcriptome analyses will be used to identify proteins that contribute to Dkk1-mediated synapse degeneration. Candidate molecules will be selected for functional studies in primary neuronal cultures. In addition, these molecules will be tested for their contribution to Dkk1-mediated synapse vulnerability. 3) To examine the in vivo role of Dkk1 target molecules. The most highly selected candidates identified in our screens will be chosen for in vivo studies. Gain and loss of function of selected candidates will be examined using viral vectors injected into the adult hippocampus of wild-type and transgenic mice expressing Dkk1. 4) To investigate the role of the Dkk1 target molecules in AD models. Behavioural studies will be performed using the most highly selected candidates from our screen to investigate the ability of these new molecules to modulate synapse degeneration in AD animal model.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Alzheimer's disease & other dementias
Years: 2016
Database Categories: N/A
Database Tags: N/A

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