The role of Klotho protein in Alzheimer's disease

Abstract

Alzheimer disease (AD) is one of the leading neurodegenerative pathologies in the western world and represents a health and socioeconomic problem. In this context , understanding the mechanisms underlying the pathogenesis of AD would be possible to identify new therapeutic options. The lost of the Endoplasmic Reticulum (ER) calcium homeostasis emerges as a central player in the development of AD. The host laboratory reported alterations of the expression and the function of Ryanodine Receptors (RyR2) channels (involved in the release of calcium from ER) in AD. The RyR2-mediated calcium leak is a consequence of post-translational modifications of RyR2 by phosphorylation, oxidation and nitrosylation. ±-Klotho is characterized as an aging-suppressor gene, and has been reported to harbor protective effects towards oxidative stress and inflammation. Even though ±-Klotho has been studied a lot since its discovery, its functions remains not completely understood especially in the brain, and in AD. The project aims to investigate if ±-Klotho could prevent RyR2 post-translational modifications and consequently decrease the oxidative stress and inflammatory response in AD models both in vitro and in a transgenic mice modeling of AD. ±-Klotho is a substrate of ±-,²- and ³-secretase (enzymes implicated in APP processing) which generates different soluble and membrane fragments. We aim to understand the specific role of each ±-Klotho fragment in the neuroprotective and/or antioxidant effect in AD models and how ±-Klotho fragments production can be controlled in AD cell models. This project will show a new molecular mechanism involved in the onset and/or progression of AD and consider ±-Klotho as a potential new therapeutic target for the treatment of AD. (AU)