Objective
Alzheimer’s disease (AD) is the most prevalent deadly neurodegenerative disorder for which no effective treatment exists as of today. Therefore, there is an urgent need to better understand the molecular mechanisms behind AD in order to develop more effective treatments against this complex disease. Recent genetic findings have highlighted several AD-associated genes, many of which are preferentially expressed in microglia in the brain. One of these is tetraspanin 14 (TSPAN14), whose physiological function in the brain is not yet understood. Recent studies suggest that TSPAN14 may act as a functional regulator of ADAM10, a transmembrane protease that cleaves multiple substrates in the brain including the AD-associated protein TREM2. Full-length TREM2 is essential for the phagocytic activity of microglia and its cleavage by ADAM10 results in loss of function. The central aim of the TSPAN14-AD project is to understand how TSPAN14 controls molecular pathways involved in AD, by focusing on proteolysis and function of TREM2. Specifically, we hypothesize that TSPAN14 increases AD risk by modulation of TREM2 cleavage and microglial phagocytosis. The 3 objectives of TSPAN14-AD are to: (1) determine whether AD-protective TSPAN14 alternative splicing variants result in reduced TSPAN14 protein expression; (2) elucidate whether reduced TSPAN14 expression results in decreased ADAM10 cell surface expression; (3) assess whether loss of TSPAN14 reduces TREM2 cleavage and enhances phagocytic activity of microglia. To accomplish this, a combination of biochemical, molecular, and proteomic techniques will be used within both in vitro and in vivo models, including human induced pluripotent stem cell (iPSC)-derived microglia and post-mortem human brain tissue. Outcomes of the project have the potential to fill in a large gap in our current understanding of molecular mechanisms leading to AD pathogenesis and may provide insight into novel therapeutic targets for AD and related disorders.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
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Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
81675 MUENCHEN
Germany