sKL/mKL Transcript Ratio and Protein Localization Define a Species- and Region-Specific Klotho Signature in the CNS and AD Progression

Rebeca Blanch; Jon Esandi; Rubén Guerrero-Yagüe; Javier del Rey; Joan Roig-Soriano; Alberto Lleó; Eva Carro; Nadine Mestre‐Francés; Gina Devau; Isidró Ferrer; Anna Meseguer; José Luis Lanciego; Beatriz Almolda; Assumpció Bosch; Miguel Chillón

doi:10.1101/2025.05.13.653838

NeurosciencebioRxivMay 13, 2025

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sKL/mKL Transcript Ratio and Protein Localization Define a Species- and Region-Specific Klotho Signature in the CNS and AD Progression

Rebeca Blanch iD, Jon Esandi iD, Rubén Guerrero-Yagüe iD, Javier del Rey iD, Joan Roig-Soriano iD, Alberto Lleó iD, Eva Carro iD, Nadine Mestre‐Francés iD, Gina Devau, Isidró Ferrer iD, Anna Meseguer iD, José Luis Lanciego iD, Beatriz Almolda iD, Assumpció Bosch iD, Miguel Chillón iD

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Abstract

-Klotho is a multifunctional protein widely recognized for its anti-aging and neuroprotective properties. This study investigates the expression and localization of the secreted Klotho (s-KL) isoform in the human brain and its potential role in Alzheimers disease. Using RT-qPCR, we observed that the s-KL transcript predominates over the membrane-bound KL (m-KL) in multiple brain regions, a pattern consistent in macaques and lemurs. Immunohistochemistry and immunoprecipitation assays confirmed the presence of the s-KL protein in human and mouse brain parenchyma, revealing species-specific cellular localization. In human cerebrospinal fluid (CSF), s-KL constitutes [~]28% of total KL, with levels significantly reduced in mild dementia-AD patients. These findings underscore s-KLs potential neuroprotective role and highlight its differential regulation and expression during AD progression.