Klotho Is a Neuroprotective and Cognition-Enhancing Protein

Abraham, Carmela R.; Mullen, Patrick; Tucker-Zhou, T; Chen, C D; Zeldich, Ella

doi:10.1016/bs.vh.2016.02.004

Cited by 69 publications

(39 citation statements)

References 88 publications

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“…While the effects of klotho and sKL on the central nervous system have been extensively studied, as reviewed elsewhere ( 77 , 248 ), it is less clear whether FGF23 can directly target neurons. A study in hippocampal neuron cultures isolated from mice shows that FGF23 treatment reduces the complex cell morphology and enhances synaptic density ( 106 ).…”

Section: Indications That Fgf23 Might Affect a Variety Of Other Tissumentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho.

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Section: Indications That Fgf23 Might Affect a Variety Of Other Tissumentioning

confidence: 99%

FGF23 Actions on Target Tissues—With and Without Klotho

2018

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“…In recent years, interest has arisen in the potential role of Klotho in the brain, including its possible protection of the central nervous system (CNS) and prevention of neurological diseases such as depression and the decline in cognitive function associated with aging. (106,107) Indeed, high levels of Klotho originating in the choroid plexus are postulated to function as a gatekeeper at the interface between the brain and immune system in the choroid plexus. (108) Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.…”

Section: G Klotho Supports Synaptic Functioning and Protects The Cenmentioning

confidence: 99%

Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25‐Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor‐23

et al. 2020

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The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D [1,25(OH)2D], produced in kidney, acts in numerous end organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target vitamin D responsive elements (VDREs) in the vicinity of vitamin D‐regulated genes. Circulating 1,25(OH)2D concentrations are governed by PTH, an inducer of renal D‐hormone biosynthesis catalyzed by CYP27B1 that functions as the key player in a calcemic endocrine circuit, and by fibroblast growth factor‐23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic endocrine loop. 1,25(OH)2D/VDR–RXR acts in kidney to induce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, and TRPV5 and CaBP28k to enhance calcium reabsorption. 1,25(OH)2D‐liganded VDR–RXR functions in osteoblasts/osteocytes by augmenting RANK‐ligand expression to paracrine signal osteoclastic bone resorption, while simultaneously inducing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, and TNAP, and conversely repressing RUNX2 and PHEX expression, effecting localized control of mineralization to sculpt the skeleton. Herein, we document the history of 1,25(OH)2D/VDR and summarize recent advances in characterizing their physiology, biochemistry, and mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR‐mediated primary induction of Klotho mRNA by 1,25(OH)2D in kidney via a mechanism initiated by the docking of liganded VDR–RXR on a VDRE at −35 kb in the mouse Klotho gene. In contrast, the secondary induction of FGF23 by 1,25(OH)2D in bone is proposed to involve rapid nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the induction of MZF1, a transcription factor that, in cooperation with c‐ets1‐P, binds to an enhancer element centered at −263 bp in the promoter‐proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D‐induced osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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“…The Klotho protein also plays an important role in protecting hippocampal neurons from amyloid formation and against glutamate toxicity by activating the antioxidant enzyme system. Furthermore, Klotho is necessary for the maturation of oligodendrocytes and the integrity of myelin [ 31 ]. Zeldich et al also demonstrated a neuroprotective effect of the secreted Klotho form on hippocampal neurons exposed to the cytotoxic activity of glutamate and beta-amyloid [ 32 ].…”

Section: Why Is Klotho Of Particular Interest For Neurodegenerative Dmentioning

confidence: 99%

Klotho protein in neurodegenerative disorders

2018

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The Klotho protein is a recently discovered protein and its overexpression is associated with life extension. Klotho deficiency or silencing of the Klotho gene in mice leads to an accelerated aging and short life, whereas overexpression of Klotho in mice extends lifespan. Klotho participates in many metabolic pathways and is highly expressed in the kidneys, the choroid plexus and neurons. It plays a key role in the calcium-phosphate metabolism, remyelination, and cognitive processes. The present paper is a short review of the literature on the role of Klotho in neurodegenerative disorders, with special attention paid to multiple sclerosis. The neuroprotective function of Klotho is also reported. It is also important to consider potential clinical applications of Klotho that might be useful in the treatment of many diseases.

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Klotho Is a Neuroprotective and Cognition-Enhancing Protein

Cited by 69 publications

References 88 publications

FGF23 Actions on Target Tissues—With and Without Klotho

FGF23 Actions on Target Tissues—With and Without Klotho

Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25‐Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor‐23

Klotho protein in neurodegenerative disorders

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