Unidentified pathways mediating Klotho’s neuroprotective effects

Identify and characterize the additional biological pathways, aside from platelet-mediated mechanisms, through which the Klotho protein confers neuroprotective effects in neurodegeneration such as Alzheimer’s disease and related dementias.

Background

Klotho is discussed as a catabolic maintenance factor that inhibits IGF-1 signaling and activates autophagy, with increased levels observed following mTOR inhibition. The paper reviews evidence that Klotho levels are inversely associated with several chronic diseases and that preclinical Klotho therapy can be beneficial.

In neurodegeneration, autophagy-mediated clearance of pathogenic proteins (e.g., amyloid-β) has been proposed as one mechanism underlying Klotho’s neuroprotection. Recent findings also indicate a role for platelets in mediating Klotho’s cognitive and neuroprotective effects. However, the authors state that additional mechanisms remain unknown, motivating the need to delineate these pathways to understand and potentially harness Klotho’s effects for therapy.