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The role of Klotho protein in Alzheimer's disease

Grant number: 18/14289-6
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2019
Effective date (End): September 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Cristoforo Scavone
Grantee:Paula Fernanda Kinoshita
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/07427-8 - Aging and neuroprotection: effects of Klotho protein in energetic metabolism, Na,K-ATPase signaling and adaptative response in central nervous system, AP.TEM
Associated scholarship(s):19/26084-2 - The role of alpha-Klotho in neuroinflammation in Alzheimer's disease, BE.EP.PD


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)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SAADE, MARINA; DE SOUZA, GIOVANNA ARAUJO; SCAVONE, CRISTOFORO; KINOSHITA, PAULA FERNANDA. The Role of GPNMB in Inflammation. FRONTIERS IN IMMUNOLOGY, v. 12, . (18/14289-6, 16/07427-8, 19/05970-4, 18/07896-3)
KAWAMOTO, E. M.; CARARO-LOPES, M. M.; KINOSHITA, P. F.; QUINTAS, L. E. M.; LIMA, L. S.; ANDREOTTI, D. Z.; SCAVONE, C.. Influence of Nitric Oxide-Cyclic GMP and Oxidative STRESS on Amyloid-beta Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices. Journal of Membrane Biology, v. 254, n. 5-6, SI, . (16/07427-8, 16/22996-9, 18/14289-6, 19/12974-6, 14/14199-6)
KINOSHITA, PAULA FERNANDA; MARQUES ORELLANA, ANA MARIA; NAKAO, VINICIUS WATANABE; DE SOUZA PORT'S, NATACHA MEDEIROS; MENEZES QUINTAS, LUIS EDUARDO; KAWAMOTO, ELISA MITIKO; SCAVONE, CRISTOFORO. The Janus face of ouabain in Na+/K+-ATPase and calcium signalling in neurons. British Journal of Pharmacology, . (16/22996-9, 19/12974-6, 16/07427-8, 18/14289-6)
YSHII, LIDIA M.; MANFIOLLI, ADRIANA O.; DENADAI-SOUZA, ALEXANDRE; KINOSHITA, PAULA F.; GOMES, MARCELO D.; SCAVONE, CRISTOFORO. Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway. IBRO REPORTS, v. 9, p. 218-223, . (12/07784-4, 11/10303-5, 14/24951-7, 09/12375-3, 18/01308-2, 16/07427-8, 19/10044-1, 18/14289-6, 13/22196-4)
VAILLANT-BEUCHOT, LOAN; MARY, ARNAUD; PARDOSSI-PIQUARD, RAPHAELLE; BOURGEOIS, ALEXANDRE; LAURITZEN, INGER; EYSERT, FANNY; KINOSHITA, PAULA FERNANDA; CAZARETH, JULIE; BADOT, CELINE; FRAGAKI, KONSTANTINA; et al. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. ACTA NEUROPATHOLOGICA, v. 141, n. 1, p. 39-65, . (18/14289-6)

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