Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice

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. [Display omitted] •A klotho fragment (αKL-F) enhances cognition in young and aging mice•αKL-F counters deficits in α-synuclein mice without altering pathogenic protein levels•αKL-F induces GluN2B cleavage and increases NMDAR-dependent synaptic plasticity•Selective NMDAR blockade of GluN2B subunits abolishes acute αKL-F effects Klotho is a longevity factor associated with cognitive enhancement when genetically and widely overexpressed over the lifetime of mice. Leon et al. show that peripheral delivery of a klotho fragment, αKL-F, acutely enhances cognition and neural resilience in young, aging, and disease model mice, establishing its therapeutic relevance and dissecting its underlying mechanisms.