All ETDs from UAB

Advisory Committee Chair

Gwendalyn D King

Advisory Committee Members

Rita Cowell

Linda Overstreet-Wadiche

Lucas Pozzo-Miller

Scott Wilson

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Klotho is an anti-aging protein that when upregulated, extends lifespan and enhances cognition. Klotho knockout mice age prematurely and die by ~8 weeks of life after developing cognitive impairment. Klotho function outside of the brain is well established but the protein’s action within the brain remains unknown. As klotho regulates peripheral stem cell populations, I sought to determine whether klotho contributes to cognition through a role in the maintenance of the adult hippocampal neurogenic niche. I examined adult mouse neurogenesis using global klotho-deficiency or global klotho overexpression models. Klotho knockout brains show reduced progenitor proliferation and granule cell production while overexpressors exhibit increased progenitor proliferation and neuron production. Beyond number, dendritic arborization of immature neurons is dramatically decreased with klotho-deficiency and enhanced with overexpression. Fate tracking and morphology analysis reveal that klotho-deficiency stalls maturation of newly committed neurons while klotho overexpressors exhibit an increase in the number of new granule cells at the most mature stage. Consistent with cellular observations in the hippocampal neurogenic niche, inverse learning and memory task performance is measured in model mice suggesting that cellular changes in the hippocampus underlie the changes measured in cognitive function. As peripheral klotho serves as a renal FGF23 co-receptor critical to phosphate regulation, FGF23 knockouts exhibit many of the same phenotypes as klotho knockouts. However, neurogenic effects are FGF23-independent as FGF23-deficient mice do not show a similar pattern of rapid neurogenic decline. These results confirm that neurogenic changes are a direct effect of klotho protein and are not a side effect of hyperphosphatemia/peripheral decline. Further, in vitro primary culture of stem and progenitor cells shows that the shed, soluble klotho isoform directly promotes neuronal precursor proliferation and restores proliferation in klotho knockout progenitors. Together, this work demonstrates klotho is a critical brain-specific protein required for cognition because of its role in maintaining the neurogenic niche.

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