The relevance of α-KLOTHO to the central nervous system: Some key questions

Cararo-Lopes, Marina Minto; Mazucanti, Caio Henrique; Scavone, Cristóforo; Kawamoto, Elisa Mitiko; Berwick, Daniel C.

doi:10.1016/j.arr.2017.03.003

Cited by 49 publications

(46 citation statements)

References 101 publications

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“…During its processing, the shed ectodomain of Klotho is released into the blood and cerebrospinal fluid and also named as soluble Klotho (sKL). Accumulating evidence indicates that this sKL may play important roles as a neuroprotective factor, thereby supporting healthy brain aging ( Hensel et al, 2016 ; Cararo-Lopes et al, 2017 ). While it has been shown that mutation of Klotho leads to systemic aging and reduced longevity in mice ( Kuro-o et al, 1997 ; Shiozaki et al, 2008 ), increasing Klotho expression has been shown to promote healthier aging and prolongation of life ( Kuro-o, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer’s Disease

Kuang

Zhou

Thorne

et al. 2017

Front. Aging Neurosci.

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Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer’s disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells. Our results show that treatment with LIG significantly ameliorated memory impairment and Aβ levels and plaques burden. Specifically, LIG might act as a potent enhancer of α-secretase, disintegrin, and metalloprotease 10 (ADAM10), leading to upregulation of alpha-processing of both APP and Klotho and subsequent increases in the levels of both soluble APP fragment (sAPPα) and soluble Klotho (sKL) with inhibition of IGF-1/Akt/mTOR signaling in AD mice and cultured cells. Moreover, the specific ADAM10 inhibitor (G1254023X) effectively reversed LIG-induced alpha-processing of both APP and Klotho in vitro, while Klotho gene knockdown by small interfering RNA significantly blunted LIG-mediated inhibition of IGF-1/Akt/mTOR signaling in vitro. Taken together with the reported neuroprotective effects of both sAPPα and sKL as well as autophagy induction by Akt/mTOR pathway inhibition, our findings suggest that neuroprotection of LIG against AD is associated with induction alpha-processing of APP and Klotho and potential Aβ clearance. Whether LIG might induce Aβ autophagic clearance and the underlying mechanisms need to be further studied.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer’s Disease

Kuang

Zhou

Thorne

et al. 2017

Front. Aging Neurosci.

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“…Variations in the klotho gene are associated with both life extension and increased cognition in human populations. The Klotho-VS polymorphism in humans for instance promotes cognition by increasing serum levels of secreted αKL (Cararo-Lopes et al, 2017). The absence of Klotho in mice causes cognitive impairment, whereas increasing Klotho improves hippocampal-dependent memory (Dubal et al, 2014(Dubal et al, , 2015.…”

Section: Introductionmentioning

confidence: 99%

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

Becke

Maaß

Kreutz

et al. 2020

Preprint

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Aerobic exercise is a potential life-style intervention to delay cognitive decline and neurodegeneration. Elevated serum levels of the anti-aging protein α-Klotho (αKL) are a potential mediating factor of exercise benefits on cognition. Here, we examined in older adults how exercise-related changes of αKL levels in serum relate to changes in cerebral blood flow (CBF), hippocampal volumes and episodic memory. We analyzed data from a previously published intervention study in which forty cognitively healthy subjects were pseudo-randomly assigned to either a cardiovascular exercise group (treadmill training, n=21) or control group (indoor progressive-muscle relaxation/stretching, n=19). 3-Tesla gadolinium perfusion imaging was used to track hippocampal CBF changes and high resolution 7-Tesla-T1-images were used to track hippocampal volume changes. Changes in episodic memory performance were measured using the complex figure test (CFT). Longitudinal changes were compared between groups and analyzed with a multiple linear regression approach. CFT and hippocampal volume changes significantly predicted changes in serum αKL levels. For CFT, this effect was found in the exercise but not the control group. Collectively the data suggest that αKL level increases induced by exercise can be associated with improved hippocampal function in older adults.

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“…4,8,[11][12][13][14][15][16] a-Klotho is often referred to as an ''anti-aging protein.'' 3,6,17,18 When overexpressed in mice, Klotho extends life (20-30%), reduces oxidative stress (OS), and demonstrates other prosurvival properties. [19][20][21][22][23][24][25] The potential of extending these results to humans has captured pharmaceutical interest in developing Klotho-based therapeutics to hinder the degenerative illnesses of aging.…”

Section: Introductionmentioning

confidence: 99%

“…[50][51][52] Beyond AD and PD, age-related declines in Klotho 8,13,17,24,53 are associated with a range of other deteriorating central nervous system (CNS) processes. 17,24 For example, mounting evidence implicates dysregulation of Klotho in shared mechanistic pathological relationships linking iron and myelin in various common and rare brain diseases, [54][55][56] including abnormalities in myelination and the maturation of oligodendrocytes that are central to the pathogenicity of diseases such as multiple sclerosis (MS) 26,56,57 and amyotrophic lateral sclerosis (ALS). 56,58 OS Demyelination and Mitochondrial Dysfunction Mitochondrial dysfunction is a well-documented enabling factor in the pathophysiology of neurological conditions and disorders ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…5,6,137,141,[144][145][146][147][148] In particular, FGF23 is a bone-derived hormone that in conjunction with Klotho acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. 5,6,14,23,102,136,138,145,148,149 Vitamin D regulates epigenetic mechanisms that maintain the transcription of its target genes in regulatory networks, including the expression of Klotho and nuclear factor-erythroid-2related factor 2 (Nrf2) to carry out many of its homoeostatic functions. 17,97,[150][151][152][153] Vitamin D is a modulator of the immune system, 154,155 hence its mention here, and accumulating evidence suggests vitamin D deficiency is a risk factor for dysregulated Klotho-associated neurodegenerative diseases, the most noteworthy being MS. 9,27,52,97,102,150,152,153,[156][157][158] Multiple Sclerosis MS is an insidious progressive neurodegenerative disease characterized by demyelinated lesions throughout the brain, spinal cord, and optic nerve resulting from immune-mediated attacks against myelin. [159][160][161]…”

Section: Introductionmentioning

confidence: 99%

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Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

Moos

Faller

Glavas

et al. 2020

BioResearch Open Access

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In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

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The relevance of α-KLOTHO to the central nervous system: Some key questions

Cited by 49 publications

References 101 publications

Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer’s Disease

Neuroprotective Effect of Ligustilide through Induction of α-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer’s Disease

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

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

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