Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus

Fanaei-Kahrani, Z.; Patel, T.; Valkova, C.; Gloria, A.; Wagner, J.; Heuer, H.; Schwaninger, M.; Hoffmann, S.; Bauer, R.; Kaether, C.

doi:10.1101/2025.11.07.686549

bioRxiv · 10.1101/2025.11.07.686549

Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus

Fanaei-Kahrani, Z.·Patel, T.·Valkova, C.·Gloria, A.·Wagner, J.·Heuer, H.·Schwaninger, M.·Hoffmann, S.·Bauer, R.·Kaether, C.

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Abstract

Klotho (Kl) is an anti-aging protein primarily produced in the kidney and the choroid plexus (CP, where it regulates cerebrospinal fluid composition and exerts neuroprotective effects. Here, we investigated the age-dependent consequences of a CP-specific Kl deletion on CP structure and function using mice lacking KL exclusively in CP epithelial cells (Kl{Delta}CP). In control mice, aging markedly disrupted CP architecture and cilia organization both in the lateral (LV-CP) and fourth ventricle (FV-CP). While CP-specific Kl deletion alone caused no major structural changes it induced region- and age-dependent calcification: FV-CP calcification increased in both aged and young Kl{Delta}CP mice, whereas LV-CP calcification emerged only in older Kl{Delta}CP mice. Proteomic analysis of the CP and hippocampus revealed mild molecular alterations, suggesting compensatory mechanisms that preserve structural and functional stability despite calcium dysregulation. Consistently, Kl{Delta}CP mice exhibited no significant behavioral or cognitive deficits. Overall, Kl deficiency sensitizes the CP to age-related calcification prior to overt structural decline, revealing a region-specific and functional link between Klotho, calcium imbalance, and brain aging.

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Fanaei-Kahrani, Z., Patel, T., Valkova, C., Gloria, A., Wagner, J., Heuer, H., Schwaninger, M., Hoffmann, S., Bauer, R., Kaether, C.. 2025-11-10. Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus. https://doi.org/10.1101/2025.11.07.686549

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