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

Blanch, R.; Esandi, J.; Guerrero-Yagüe, R.; Del Rey, J.; Roig-Soriano, J.; Lleo, A.; Carro, E.; Mestre-Frances, N.; Devau, G.; Ferrer, I.; Meseguer, A.; Lanciego, J. L.; Almolda, B.; Bosch, A.; Chillon, M.

doi:10.1101/2025.05.13.653838

bioRxiv · 10.1101/2025.05.13.653838

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

Blanch, R.·Esandi, J.·Guerrero-Yagüe, R.·Del Rey, J.·Roig-Soriano, J.·Lleo, A.·Carro, E.·Mestre-Frances, N.·Devau, G.·Ferrer, I.·Meseguer, A.·Lanciego, J. L.·Almolda, B.·Bosch, A.·Chillon, M.

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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.

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Blanch, R., Esandi, J., Guerrero-Yagüe, R., Del Rey, J., Roig-Soriano, J., Lleo, A., Carro, E., Mestre-Frances, N., Devau, G., Ferrer, I., Meseguer, A., Lanciego, J. L., Almolda, B., Bosch, A., Chillon, M.. 2025-05-17. sKL/mKL Transcript Ratio and Protein Localization Define a Species- and Region-Specific Klotho Signature in the CNS and AD Progression. https://doi.org/10.1101/2025.05.13.653838

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