Research progress in the role of hippocampal Klotho in improving cognitive function and neuroprotection
Cognitive dysfunction is a key symptom of aging and neurodegenerative diseases,such as Alzheimer's disease(AD).Improving the cognitive function favors the quality of life in the elderly.The deficiency of Klotho shortens the lifespan of mice and leads to various complications associated with premature aging.Klotho can prevent age-related cognitive decline and neurodegenerative diseases through multiple mechanisms,including the binding to the fibroblast growth factor(FGF)receptor FGF23 on the renal tubule.FGF23 is a bone-derived hormone that regulates renal excretion of phosphate and vitamin D metabolism.It promotes optimal synaptic function by activating the N-methyl-D-aspartate(NMDA)receptor signaling.Moreover,FGF23 mediates neuronal antioxidant effect by inhibiting the insulin-like growth factor 1(IGF-1)signaling pathway,reducing the expression of phosphorylated forkhead box transcription factor 3a(p-FOXO3a)and phosphorylated protein kinase B(p-AKT),and upregulating the expression of superoxide dismutase-2(SOD2).FGF23 is also functional in stimulating antioxidant defense system,reducing inflammation,promoting autophagy,enhancing the clearance of amyloid-β,inhibiting thioredoxin-interacting protein/NOD-like receptor protein 3(TXNIP/NLRP3)inflammasome,expressions of cytokines interleukin-1 beta(IL-1β)and interleukin-18(IL-18)and ferroptosis.Peripheral administration of Klotho also improves cognitive function.Some drugs like formononetin,resveratrol,carbachol,and atracurium improve cognitive function via upregulating Klotho.Exercise and diet can also regulate Klotho levels,which needs further research.This review introduces the biological function of Klotho and the molecular mechanisms involved in neuroprotection and cognition improvement.
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