The relevance of α-KLOTHO to the central nervous system: Some key questions

alpha-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. alpha-Moth is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, alpha-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of alpha-Klotho, which we define as brain alpha-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain alpha-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain alpha-Klotho and other pools of alpha-Klotho, and for a greater understanding of the basic function of soluble alpha-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of alpha-Klotho for the aging brain to become clear. (C) 2017 Published by Elsevier B.V.