|Year : 2019 | Volume
| Issue : 1 | Page : 1-6
Klotho: An emerging factor in neurodegenerative diseases
Gauri V Pathare, Kavita K Shalia
Department of Biochemistry, Sir H. N. Medical Research Society, Mumbai, Maharashtra, India
|Date of Web Publication||24-Apr-2019|
Ms. Gauri V Pathare
Sir H. N. Medical Research Society, Court House, L. T. Road, Mumbai - 400 002, Maharashtra
Source of Support: None, Conflict of Interest: None
Soluble Klotho protein is present in blood, urine, and cerebrospinal fluid and works as a humoral factor exerting different biological effects. Several animal studies have demonstrated the association of age-related neurodegeneration with Klotho deficiency. Lower Klotho levels have been reported in patients suffering from cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurodegenerative diseases. Due to its antiaging properties, Klotho is the obvious choice to be studied as a protective/therapeutic agent in neurobiology. In this review, we have attempted to shed light on the different neurodegenerative diseases affected by deficiency of Klotho and its neuroprotective role against pathogenicity of the disease.
Keywords: Alzheimer's disease, cognitive impairment, Klotho, multiple sclerosis, oxidative stress, Parkinson's disease
|How to cite this article:|
Pathare GV, Shalia KK. Klotho: An emerging factor in neurodegenerative diseases. Biomed Res J 2019;6:1-6
| Introduction|| |
The Klotho protein discovered over two decades ago is still a sought after molecule. Although its protective effects on physiology can be observed and have been demonstrated in several animal and human studies, its mechanism remains an enigma. Hence, even today, it can be referred to as “novel” as described by its discoverer in 1997. Studies on Klotho have been commenced in almost all human pathophysiological disorders. Due to its antiaging properties, it is the obvious choice to be studied as a protective/therapeutic agent in neurobiology. In this review, we have attempted to shed light on the different neurodegenerative diseases affected by deficiency of Klotho. The role of Klotho in these diseases is briefly described in [Figure 1].
|Figure 1: Role of Klotho in neurodegenerative diseases (Abbreviations: Aβ: β-amyloid, AHN: Adult hippocampal neurogenesis, CSF: cerebrospinal fluid, OS: Oxidative stress, RRMS: Relapsing-remitting multiple sclerosis, SNC: Substantia nigra pars compacta)|
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| Klotho Gene and Protein|| |
Kuro-o et al. have established a novel mouse autosomal recessive mutant, deficient in the Klotho gene, which exhibits multiple phenotypes very similar to those observed during human aging, which can be regarded as a model of human premature aging syndromes. The human Klotho gene (KL), more precisely α-Klotho, located on chromosome 13q12, spans over 50 kb in length, and comprises five exons and four introns. It is expressed primarily in the kidney, the parathyroid gland, and the choroid plexus in the brain., The Klotho gene encodes two transcripts that arise from alternative RNA splicing. The full-length transcript encodes a single-pass membrane protein (KL) that consists of (1) an N-terminal signal sequence, (2) an extracellular domain with two internal repeats (KL1 and KL2), (3) a single-pass transmembrane protein, and (4) a short intracellular carboxy-terminal domain. The membrane form acts as co-receptor for bone-derived fibroblast growth factor-23 (FGF-23), thereby regulating phosphate and Vitamin D metabolism. The other transcript encodes a truncated KL protein lacking the second internal repeat of the extracellular domain (KL2), the transmembrane domain, and the intracellular domain. This soluble form is also produced by cleavage of extracellular domain of the transmembrane protein by proteases (ADAM10 and ADAM17). This soluble form is found to predominate over the membrane form and was concluded to be the major gene product in humans by Matsumura et al. The soluble Klotho is present in blood, urine, and cerebrospinal fluid (CSF) and works as a humoral factor exerting different biological effects and works independently of FGF-23 signaling. Circulating Klotho plays an important role in the regulation of endothelial maintenance through regulation of nitric oxide availability,, calcium homeostasis in the kidney,, and inhibition of intracellular insulin and insulin-like growth factor-1 signaling.
| Klotho and Neuroprotection|| |
Klotho expression is downregulated with age.,,, Recent years have seen a surge in the studies exploring the effects of lack as well as potential therapeutic effect of Klotho in age-related changes in the brain. Shiozaki et al. have proposed that Klotho knockout mouse is an apt model to study the central nervous system (CNS) aging. Studies have reported CNS alterations such as hypomyelination, overexpression/phosphorylation of neurofilaments, synaptic loss, and behavioral impairments in Klotho-deficient mice similar to those observed in aged animals.,, Moreover, selective reduction of Klotho levels in the choroid plexus in the brain promoted neuroinflammation. So, how does Klotho protect the brain?
The common link between aging and neuropathological changes including cognitive deficits is “oxidative stress.” Vascular risk factors such as atrial fibrillation, hypertension, atherosclerosis, angina, and diabetes – whose pathogenesis has been attributed to oxidative stress – have also been reported to contribute in dementia and Alzheimer's disease (AD). Therefore, the answer to how Klotho, as an antiaging protein, ameliorates such pathologies, could be by its ability to resist oxidative stress. In fact, its ability to induce expression of antioxidative enzymes via the inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling is the main pathway through which Klotho functions is an antiaging factor. Suppression of insulin/IGF-1 signaling is an evolutionarily conserved mechanism for longevity. However, there are no reports yet on the actual mechanism by which Klotho inhibits the activity of insulin/IGF-1 receptors in the brain.
Another way Klotho influences aging process in the brain is via regulation of Vitamin D synthesis. Although global Vitamin D3 deficiency is a risk factor for age-related cognitive decline, hypervitaminosis D is a risk factor for cognitive impairment., Klotho here controls hypervitaminosis D by inhibiting the enzyme 1-α-hydroxylase that catalyzes the formation of 1,25-dihydroxyvitamin D3, the bioactive form of Vitamin D. Thus, Klotho plays an important role in proper functioning of the CNS.
| Klotho Deficiency and Cognitive Impairment/decline|| |
The reduced levels of Klotho as well as IGF-1 in the hippocampus of rat model of dementia suggests a significant role of these molecules in the pathogenesis of dementia. Dubal et al. observed that mice with increased Klotho levels showed improved long-term potentiation (strengthening of synapses), as well as increased synaptic GluN2B (an N-methyl-D-aspartate receptor subunit, with vital learning and memory functions). They further reported that Klotho elevated this essential synaptic GluN2B through post-transcriptional mechanisms in a subunit-specific manner. The Klotho-mediated positive effects were, however, lost on blocking GluN2B. A comparison between Klotho overexpressing and control mice in their study showed that increased Klotho enhanced learning and memory in various tasks without any behavioral alteration. In fact, this suggested that the effect of elevated Klotho on survival, longevity, and improved cognition in mice is independent of age.
A comparison study by Nagai et al. between Klotho mutant mice and wild-type mice for mnemonic function associated with aging, measured by an object recognition memory task requiring the hippocampus, showed that cognitive impairment was evident in the Klotho mutant mice. Increased lipid and DNA peroxide levels in the brain of Klotho mutant mice were found prior to the development of evident cognition deficits, suggesting a role for oxidative stress in the etiology of aging-associated cognitive impairment. Supporting this hypothesis was the fact that lowering oxidative stress in Klotho mutant mice with α-tocopherol, an antioxidant that reduces lipid peroxidation, was accompanied by prevention of apoptotic cell death in the hippocampus, and mitigation of memory impairment. Klotho expression has been reported in adult hippocampus and has been associated with hippocampal cognitive performance in mammals. Adult hippocampal neurogenesis (AHN), an evolutionarily conserved mechanism in humans, is vital for several hippocampal cognitive processes including pattern separation, contextual fear conditioning, and spatial memory. Salech et al. have reported Klotho expression in the granular layer of the adult dentate gyrus (DG) of the hippocampus. Downregulating Klotho in the hippocampus decreased AHN and led to poorer hippocampal-dependent memory. On the other hand, providing recombinant Klotho accelerated the proliferation of neural progenitors. This study proposed Klotho's direct involvement in regulating AHN, thereby making it indispensable for cognitive functions.
Laszczyk et al. suggested that Klotho is required for neurogenesis during the transition to adult brain functionality. Although they found that the highest expression of Klotho was observed in choroid plexus, mature hippocampal neuronal layers, including the DG, also expressed the protein. They further showed that the deficiency of Klotho in the hippocampus led to reduced numbers of neural stem cells, decreased proliferation, and impaired neuronal maturation, which collectively led to premature aging. Moreover, Klotho deficiency led to a smaller size and reduced proliferation in neurospheres, which were rectified by providing recombinant Klotho. Thus, the study suggested a regulatory role of Klotho in postnatal neurogenesis, including neural stem cell proliferation and maturation. Supporting this conclusion, was the evident influence of Klotho on hippocampal-dependent spatial memory function.
To test the validity of Klotho as a neuroprotective agent, Zhou et al. injected a lentiviral vector, encoding the Klotho gene, into the bilateral lateral ventricles of 7-month-old senescence-accelerated mouse prone 8 (SAMP8) animals. The mice were observed for a period of 3 months, at the end of which the Y-maze alternation task and passive avoidance task were used to assess their memory deficits. They reported a significant increase in the Klotho expression in the brain of SAMP8 mice at 10 months, along with reduced memory deficits, neuronal loss, and synaptic damage. Further, increased expression of antioxidative enzymes (manganese superoxide dismutase and catalase), attributed to decreased Akt and forkhead box class O1 (FoxO1) phosphorylation, was caused by the upregulation of Klotho expression. Thus, Zhou et al. demonstrated that direct upregulation of Klotho in the brain may ameliorate age-related memory impairments possibly by curtailing oxidative stress.
Further, the protective effects of Klotho were established through an experiment by Long et al. Ligustilide, a phthalide derivative, found in several medicinal plants minimizes the cognitive dysfunction and brain damage induced by cerebral ischemia. It provides neuroprotection against cerebral ischemia in mice by regulating anti-inflammatory and antioxidant signaling pathways. Long et al. downregulated Klotho in the choroid plexus tissues by injecting lentiviruses into a specific location in the bilateral common carotid artery occlusion (BCCAO) mouse model of cerebral ischemia. They found ligustilide to upregulate the expression of Klotho in the choroid plexus. Moreover, downregulation of Klotho attenuated the protective effects of ligustilide on neurons in the hippocampus and caudate-putamen regions of mice with BCCAO-induced neural injury. Furthermore, silencing of Klotho gene prevented the inhibitory effects of ligustilide on the RIG-1/nuclear factor kappa-B p65 and Akt/FoxO1 pathways. Thus, they concluded that Klotho upregulation might contribute to the ligustilide-induced neuroprotection after cerebral ischemic injury in mice.
The protective effects of Klotho have also been reported in dementia. In dementia model of rats, Wang et al. observed that Klotho levels were reduced at the hippocampus and suggested a relationship between Klotho and pathogenesis of dementia. Participants from the population-based “Invecchiare in Chianti” or “Aging in Chianti” (InCHIANTI) study, a prospective cohort study comprising Italian adults over 55 years of age and without dementia, were recruited by Shardell et al. Their study demonstrated an independent association between higher plasma Klotho concentrations and lesser cognitive decline, as measured by the Mini-Mental State Examination. Similar results were reported by Zou and Zhou in a case–control study which indicated lower Klotho protein levels to be associated with mild cognitive impairment (MCI) in aged individuals. Further genetic studies by the same group have identified the contribution of promoter methylation of the Klotho gene to MCI in Xinjiang Han population in China. Modifications in promoter methylation are often found to affect gene expression and have been associated with neurodegenerative diseases. They have further reported the difference in Klotho protein levels, and Klotho promoter hypermethylation-related risk varies according to different ethnic groups. Thus, further investigation pertinent to the ethnicity-related risks is required.
| Klotho in Neurodegenerative Diseases|| |
Multiple sclerosis (MS) is the most common neurodegenerative disease that results from inflammatory demyelinating events. MS is characterized by a loss of oligodendrocytes (with partial protection of axons), astroglial scars, and multiple demyelinization areas. Chen et al. found a direct correlation between Klotho protein and oligodendrocyte maturation and myelination of the CNS in murine models. Moreover, their Klotho knockout mice showed a significant reduction in major myelin protein and gene expression levels as well as significantly lower mature oligodendrocytes. Thus, Klotho evidently plays a key role in myelin biology and maybe a key therapeutic target involved in protecting myelin against age-dependent changes in the brain.
In humans, Emami Aleagha et al. found decreased Klotho concentration in the CSF of patients with relapsing-remitting MS (RRMS). Furthermore, they reported that Klotho levels showed a significant negative correlation with the Expanded Disability Status Scale. It has been established through several studies that the redox system plays an important role in the pathophysiology of neurodegenerative diseases. The authors also found evidence supporting this wherein they found total antioxidant capacity in the CSF to be low in patients suffering from RRMS as compared to controls as well as positively correlated to Klotho levels.
Contrarily, increased serum Klotho levels were found in MS patients as compared to controls by two independent studies. As part of the FGF-23/Klotho axis, Klotho is involved in regulation of Vitamin D synthesis, which has been reported to play a role in the progression and prevalence of MS. A lower risk of MS in individuals exposed to sunlight in early life supports this theory. Vitamin D has been shown to have immunomodulatory effects on an experimental model of MS by Muthian et al. Ellidag et al. observed lowered Vitamin D levels and elevated serum Klotho and FGF-23 levels in MS patients as compared to controls. On this basis, they concluded that the Klotho/FGF-23/Vitamin D axis is altered in MS and has a significant role in the pathogenesis and progression of the disease. Similar elevated serum Klotho levels in MS have been reported by Ahmadi et al. However, they have attributed this to the use of immunomodulatory drugs in the treatment of MS or a compensatory response to increase CNS regeneration via Vitamin D biosynthesis.
The formation of senile plaques consisting of the β-amyloid (Aβ) peptides is a hallmark feature of AD pathogenesis. It is generated via amyloidogenic processing of the amyloid precursor protein (APP), which also generates secreted ectodomain fragments (APPsα and APPsβ), and an APP intracellular domain. Although the precise physiological function of APP is not known, APP overexpression shows a neurotrophic effect on neural cell health and growth. Klotho is a physiological target of APP whose expression is mediated by APPsβ. Li et al. proposed that extracellular APP processing produces APP ectodomain derivatives, which promote Klotho expression and protect against Aβ neurotoxicity during aging. Moreover, L-glutamate (major excitatory neurotransmitter) and Aβ are widely used as oxidative stressors in in vitro models of neurodegeneration for studying neuronal damage mechanisms. The neurotoxic effect of Aβ is also associated with cellular injury resulting from reactive oxygen species exposure. Zeldich et al. showed that Klotho protects hippocampal neurons which have the highest vulnerability to oxidative stress, from glutamate and oligomeric Aβ-induced toxicity. This protection could be achieved by providing exogenous Klotho or increasing endogenous Klotho levels as found in Klotho-overexpressing mice.
In a study conducted in aged individuals, Semba et al. found significantly lower CSF Klotho concentrations in those with AD as compared to those with normal cognition. They also found CSF Klotho concentrations to be lower in older as compared to younger individuals. In addition, they reported higher CSF Klotho concentrations in men than women, an interesting finding considering the higher risk and incidence of the disease associated with women. Similar favorable results for Klotho were observed by Yokoyama et al., where they found higher serum Klotho levels to be associated with greater intrinsic connectivity in key functional networks (such as frontoparietal and default-mode networks) of the brain vulnerable to age-dependent neurodegeneration as well as AD. Their findings suggested the role of Klotho in maintaining and promoting brain resilience to neurodegeneration, which was possibly facilitated by boosting network connectivity of the prefrontal and temporal cortex.
As Klotho has been shown to protect neurons against oxidative stress, it could be applied to the prevalent movement disorder in the elderly, Parkinson's disease (PD). Clinically, PD is characterized by deteriorating motor functions such as resting tremor, difficulty with coordination, muscle rigidity, stooping posture, and bradykinesia. Increased oxidative stress, reduced antioxidant status, and inflammation mediated by protein kinase A (PKA)-dependent cascade play critical roles in PD pathogenesis.
Loss of dopamine neurons in the substantia nigra pars compacta (SNC) is one of the main pathological features of PD. The nigrostriatal pathway is a dopaminergic pathway that connects the SNC with the dorsal striatum. Baluchnejadmojarad et al. carried out an experiment to determine the ability of exogenous Klotho to mitigate the damage to nigrostriatal dopaminergic pathway in 6-hydroxydopamine (6-OHDA) rat model of PD. They demonstrated that pretreating rats with Klotho alleviated drug-induced rotational behavior of 6-OHDA-lesioned rats and improved their performance in narrow beam task. At the cellular level, Klotho prevented degeneration of tyrosine hydroxylase-positive neurons in the SNC. In addition, Klotho significantly ameliorated α-synuclein, glial fibrillary acidic protein, phosphorylated-cAMP-response element binding protein (CREB), DNA fragmentation, and oxidative stress. Moreover, the beneficial effect of Klotho was reportedly attenuated by administering a PKA inhibitor and Ca2+/calmodulin-dependent protein kinase II (CamKII) inhibitor. Thus, the neuroprotective effect of Klotho in 6-OHDA rat model of PD appears to be dependent on PKA/CaMKII/CREB signaling cascade.
Synuclein is an important membrane protein in the pathogenesis of PD, which is responsible for regulating the exocytosis mechanisms. Overexpression of human α-synuclein (hSYN) in transgenic mice leads to accumulation of α-synuclein in neurons and synapses and manifests as motor and cognitive deficits in the mice, thereby simulating key aspects of neurodegenerative diseases. Leon et al. demonstrated that soluble Klotho could counteract cognitive deficits in this disease model. Moreover, peripheral Klotho treatment enhanced synaptic functions and brain resilience in these mice. Thus, studying the protective effects of Klotho in mice can lead to potentially promising therapeutic strategies for humans in aging and neurodegenerative diseases.
| Conclusion|| |
Neuronal cell death, particularly resulting from increased oxidative stress, has been implicated as a major risk factor for neurodegenerative diseases. The essential role of Klotho to counteract the same in healthy brain aging, its neuroprotective properties, and its ability to ameliorate neuronal damage associated with neurodegeneration have been evidenced in several studies. Klotho may even have immune-regulatory roles in the choroid plexus of the brain. Klotho-dependent pathways are impaired with normal aging but more so with neurodegenerative disease development. Thus, Klotho is instrumental in counteracting cognitive decline and age-related neurological disorders. The need of the hour is to investigate the therapeutic potential of Klotho for neurological disorders.
Financial support and sponsorship
The authors would like to acknowledge Sir H. N. Medical Research Society, Mumbai, India, for financial support.
Conflicts of interest
There are no conflicts of interest.
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