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Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11388-E11396. doi: 10.1073/pnas.1808609115. Epub 2018 Nov 9.

Klotho controls the brain-immune system interface in the choroid plexus.

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Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158.
Nephrology Unit, Department of Clinical Science, Intervention and Technology, Karolinska Institute, M 99 141 86 Stockholm, Sweden.
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158;
Department of Neurology, University of California, San Francisco, CA 94158.


Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.


aging; choroid plexus; inflammation; klotho; macrophage

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