Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice
Julio Leon,
Arturo J. Moreno,
Bayardo I. Garay,
Robert J. Chalkley,
Alma L. Burlingame,
Dan Wang,
Dena B. Dubal
Affiliations
Julio Leon
Department of Neurology, Biomedical Sciences Graduate Program, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Arturo J. Moreno
Department of Neurology, Biomedical Sciences Graduate Program, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Bayardo I. Garay
Department of Neurology, Biomedical Sciences Graduate Program, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Robert J. Chalkley
Department of Chemistry and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
Alma L. Burlingame
Department of Chemistry and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
Dan Wang
Department of Neurology, Biomedical Sciences Graduate Program, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Dena B. Dubal
Department of Neurology, Biomedical Sciences Graduate Program, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
Cognitive dysfunction and decreased mobility from aging and neurodegenerative conditions, such as Parkinson and Alzheimer diseases, are major biomedical challenges in need of more effective therapies. Increasing brain resilience may represent a new treatment strategy. Klotho, a longevity factor, enhances cognition when genetically and broadly overexpressed in its full, wild-type form over the mouse lifespan. Whether acute klotho treatment can rapidly enhance cognitive and motor functions or induce resilience is a gap in our knowledge of its therapeutic potential. Here, we show that an α-klotho protein fragment (αKL-F), administered peripherally, surprisingly induced cognitive enhancement and neural resilience despite impermeability to the blood-brain barrier in young, aging, and transgenic α-synuclein mice. αKL-F treatment induced cleavage of the NMDAR subunit GluN2B and also enhanced NMDAR-dependent synaptic plasticity. GluN2B blockade abolished αKL-F-mediated effects. Peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans.
