Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Abstract

Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6 month old klotho overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggest direct, local effects of the protein. Together these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function.

Serum α-Klotho levels correlate with episodic memory changes related to cardiovascular exercise in older adults

“…Collectively, the data support the possibility that αKL serum level increases can improve hippocampal plasticity and could thereby impact cognition and hippocampal function in aged persons. This effect of αKL on HC VOL is in line with findings that Klotho is an important factor for the maturation of hippocampal neurons with impact on hippocampal-dependent spatial memory function (Laszczyk et al, 2017).…”

“…Since elevating Klotho serum levels in mice enhances cognition (Dubal et al, 2014(Dubal et al, , 2015Leon et al, 2017), strategies that increase Klotho activity or simulate its function may therefore improve cognition at different life stages and, possibly, even under pathological circumstances. Recent evidence suggests that Klotho is a regulator of postnatal neurogenesis, affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function (Laszczyk et al, 2017).…”

“…Premature aging of the klotho-deficient hippocampal neurogenic niche is evident by a reduced number of neural stem cells, decreased proliferation, and impaired maturation of immature neurons (Laszczyk et al, 2017). Conversely, 6-months-old KLoverexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization.…”

Klotho, the Key to Healthy Brain Aging?

“…The brain’s white matter tracts, containing neuronal axons, their associated myelin sheaths, and myelin maintaining oligodendrocytes, are particularly prominent sites for downregulation of KL with age [ 12, 13 ]. The volume of the major hippocampal output white matter tract, the fimbria, is dramatically decreased over KL-deficient mouse lifespan and this correlates with fewer oligodendrocytes [ 56–58 ]. Axon analysis across CNS white matter tracts of KL-deficient mice show impaired myelination [ 57 ].…”

Klotho gene polymorphism, brain structure and cognition in early-life development

“…The initial increase in volume may relate to dendritic arborisation (Giedd 2004 ), while the subsequent decrease likely reflects dendritic pruning processes (De Bellis et al 2001 ). Previous work in mice has shown that klotho plays a role in neurodevelopment, including myelination (Chen et al 2013 ), synaptic function (Dubal et al 2014 ) and dendritic arborization (Laszczyk et al 2017 ).…”