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

Lei Zhu1, Liana R Stein1, Daniel Kim1

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Aging reduces klotho protein in the brain's choroid plexus, weakening its barrier function. This depletion promotes inflammation and immune cell infiltration, potentially driving neuropathogenesis.

Keywords:
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Area of Science:

  • Neuroscience
  • Immunology
  • Endocrinology

Background:

  • The choroid plexus, located in brain ventricles, produces cerebrospinal fluid and acts as a crucial barrier.
  • High levels of the protein klotho are produced by the choroid plexus, but decrease with aging.
  • The precise function of choroid plexus-derived klotho remains largely unknown.

Purpose of the Study:

  • To investigate the role of klotho in the choroid plexus and its implications in aging and brain immunity.
  • To determine the effects of klotho depletion on the choroid plexus barrier integrity and inflammatory responses.

Main Methods:

  • Utilized targeted viral vector-induced knockout of klotho in Klothoflox/flox mice.
  • Administered lipopolysaccharide to assess microglial activation in the hippocampus.
  • Performed primary cell cultures to examine klotho's effect on NLRP3 inflammasome activation.

Main Results:

  • Selective klotho depletion in the choroid plexus of young mice mimicked age-related increases in proinflammatory factors and macrophage infiltration.
  • Klotho depletion enhanced microglial activation in the hippocampus following peripheral immune challenge.
  • Klotho suppressed NLRP3 inflammasome activation in macrophages via fibroblast growth factor 23 signaling.

Conclusions:

  • Klotho acts as a critical gatekeeper protein at the choroid plexus interface between the brain and the immune system.
  • Age- or disease-related klotho depletion may compromise the brain barrier, promoting neuroinflammation and neuropathogenesis.