Anti-aging Klotho Protects SH-SY5Y Cells Against Amyloid β1–42 Neurotoxicity: Involvement of Wnt1/pCREB/Nrf2/HO-1 Signaling (original) (raw)
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Klotho increases antioxidant defenses in astrocytes and ubiquitin–proteasome activity in neurons
Scientific Reports
Klotho is an antiaging protein, and its levels decline with age and chronic stress. The exogenous administration of Klotho can enhance cognitive performance in mice and negatively modulate the Insulin/IGF1/PI3K/AKT pathway in terms of metabolism. In humans, insulin sensitivity is a hallmark of healthy longevity. Therefore, this study aimed to determine if exogenous Klotho, when added to neuronal and astrocytic cell cultures, could reduce the phosphorylation levels of certain insulin signaling effectors and enhance antioxidant strategies in these cells. Primary cell cultures of cortical astrocytes and neurons from mice were exposed to 1 nM Klotho for 24 h, with or without glucose. Klotho decreased pAKT and mTOR levels. However, in astrocytes, Klotho increased FOXO-3a activity and catalase levels, shielding them from intermediate oxidative stress. In neurons, Klotho did not alter FOXO-3 phosphorylation levels but increased proteasome activity, maintaining lower levels of PFKFB3. This ...
Journal of Molecular Neuroscience, 2019
Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by neural inflammation and oxidative stress. In the current study, the protective effects of klotho and linagliptin treatment on human peripheral blood mononuclear cells (PBMCs) of AD patients and healthy controls (HCs) are assessed through measurement of inflammatory cytokines, signaling proteins, and miRNA expression. Sixteen diagnosed AD patients and sixteen HCs were enrolled in the study. Blood samples were obtained and PBMCs were isolated. PBMCs were treated with klotho at different concentrations (0.5, 1, and 2 nM) and linagliptin (50 μM). The concentration of interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), epsilon isoform of protein kinase C (PKCε), phosphorylated cyclic AMP response element binding (pCREB), and Wnt1 were measured by ELISA. The expression of miR-29a and miR-195 was detected by real-time PCR. The results showed that klotho significantly reduced IL-1β, IL-6, and TNF-α levels in both groups of the experiment. Linagliptin also remarkably reduced TNF-α levels in the AD group. Moreover, klotho caused the downregulation of Wnt1 in the PBMCs of both groups and the upregulation of the pCREB in HCs. Meanwhile, klotho induced miR-29a expression in the PBMCs of HCs, while miR-29a expression was induced in the AD group by klotho and linagliptin. The current findings revealed that klotho alleviates inflammation in human PBMCs, probably through the suppression of inflammatory cytokines and the upregulation of miR-29a, and part of its beneficial effect is mediated through appropriate modulation of the Wnt1/pCREB signaling cascade. In addition, linagliptin exerts protective effects by reducing TNF-α and inducing miR-29a expression in PBMCs.
The α-Klotho is an anti-aging protein that when overexpressed extends the life span in humans and mice. It has an anti-inflammatory and protective action on renal cells by inhibiting NF-κB activation and production of inflammatory cytokines in response to TNF-α. Furthermore, studies have shown the neuroprotective effect of α- α-Klotho against neuroinflammation on different conditions, such as aging, animal models of neurodegenerative diseases, and ischemic brain injury. This work aimed to evaluate the effects of α- α-Klotho protein on primary glial cell culture against the proinflammatory challenge with LPS and how this could interfere in neuronal health. Cortical mixed glial cells and purified astrocytes were pretreated with α- α-Klotho and stimulated with LPS followed by TNFα, IL-1β, IL-6, IFN-γ levels and NF-κB activity analysis. Conditioned medium from cortical mixed glia culture treated with LPS (glia conditioned medium (GCM) was used to induce neuronal death of primary cortica...
PLOS ONE, 2015
Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal levels of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the transgene corresponds to higher level of ASK1-bound Trx, while the KO mice showed elevated p38 activation and lower level of-bound Trx; and 3) that 14-3-3ζ is hyper phosphorylated (Ser-58) in the transgene which correlated with increased monomer forms. In addition, we evaluated the in vivo robustness of the protection by challenging the brains of Klotho transgenic mice with a neurotoxin, MPTP and analyzed for residual neuron numbers and integrity in the substantia nigra pars compacta. Our results show that Klotho overexpression significantly protects dopaminergic neurons against oxidative damage, partly by modulating p38 MAPK activation level. Our data highlight the importance of ASK1/p38 MAPK pathway in the brain and identify Klotho as a possible anti-oxidant effector.
Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells
Biochemical and Biophysical Research Communications, 2006
Klotho-mutated mice manifest multiple age-related disorders that are observed in humans. A recent study suggested that Klotho protein might function as an anti-aging hormone in mammals. Because it has been reported that apoptosis and senescence in vascular endothelial cells are closely related to the progression of atherosclerosis, we investigated KlothoÕs ability to interfere with apoptosis and cellular senescence in human umbilical vascular endothelial cells (HUVEC). Klotho overexpression decreased H 2 O 2-induced apoptosis in COS-1 cells and Jurkat cells. Klotho protein also reduced H 2 O 2-and etoposide-induced apoptosis in HUVEC. Caspase-3 and caspase-9 activity was lower in Klotho-treated HUVEC than in control cells. Senescence-associated b-gal staining showed that Klotho protein interferes with H 2 O 2-induced premature cellular senescence. The expression of p53 and p21 was lower in Klotho-treated cells. Our study suggests that Klotho acts as a humoral factor to reduce H 2 O 2-induced apoptosis and cellular senescence in vascular cells.
Klotho, the Key to Healthy Brain Aging?
Brain expression of klotho was first described with the initial discovery of the klotho gene. The prominent ageregulating effects of klotho are attributed to regulation of ion homeostasis through klotho function in the kidney. However, recent advances identified brain functions and cell populations, including adult hippocampal neural progenitors, which require klotho. As well, both human correlational studies and mouse models of disease show that klotho is protective against multiple neurological and psychological disorders. This review focuses on current knowledge as to how the klotho protein effects the brain.
Vascular protective effects of KLF2 on Aβ-induced toxicity: Implications for Alzheimer's disease
Brain research, 2017
Alzheimer's disease (AD) is characterized by excessive amounts of senile plaques and neurofibrillary tangles in the brain, and cerebrovascular pathologies in AD are attracting increasingly more attention. Krüppel-like factor (KLF) 2, a transcription regulator expressed in the mouse embryonic vasculature and involved in the regulation of vascular gene expression, serves as a protective factor in endothelial cells. However, whether KLF2 is involved in neurodegenerative disease, and especially in AD, remains unknown. In the present study, the effects of KLF2 in Aβ-induced neurotoxicity were investigated. Firstly, we found that KLF2 expression decreased at both the RNA and protein levels in AD cases. The following results show that KLF2 was found to be decreased in both a time- and dose-dependent manner in response to Aβ1-42 treatment in primary mouse brain microvascular endothelial cells. Overexpression of KLF2 attenuated Aβ-induced oxidative stress, improved mitochondrial function...
Journal of Molecular Neuroscience, 2018
Recently, we reported a positive correlation between Klotho, as an anti-aging protein, and the total antioxidant capacity (TAC) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. However, there is no information about the Klotho and TAC changes within the central nervous system (CNS). Thus, the current study aimed to employ an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice using MOG 35-55 peptide to examine the relationship between Klotho and TAC within the CNS. To this end, the brain and spinal cord were obtained at the onset and peak stages of EAE as well as non-EAE mice (sham/control groups). The Klotho expression was assessed in the brain and spinal cord of different experimental groups at mRNA (qPCR) and protein (ELISA) levels. Also, TAC level was determined in the tissues of different experimental groups. The results showed that Klotho expression in the brain at the onset and peak stages of EAE were significantly lower than that in non-EAE mice. Conversely, Klotho expression in the spinal cord at the onset of EAE was significantly higher than that of non-EAE mice, while Klotho was comparable at the peak stage of EAE and non-EAE mice. The pattern of TAC alteration in the brain and spinal cord of EAE mice was similar to that of Klotho expression. In conclusion, for the first time, this study demonstrated a significant positive correlation between Klotho and TAC changes during the pathogenesis of EAE. It is suggested that Klotho may have neuroprotective activity through the regulation of redox system.
NF-κB pathway: a target for preventing β-amyloid (Aβ)-induced neuronal damage and Aβ42 production
European Journal of Neuroscience, 2006
Beta-amyloid (Aβ) peptides are key proteins in the pathophysiology of Alzheimer's disease (AD). While Aβ42 aggregates very rapidly to form early diffuse plaques, supplemental Aβ40 deposition is required to form mature neuritic plaques. We here investigated the role of nuclear factor-κB (NF-κB) pathway in Aβ40-mediated neuronal damage and amyloid pathology. In rat primary neurons and human postmitotic neuronal cells, the Aβ peptide induced a dose-dependent neuronal death, reduced the levels of the anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c, and elicited the intracellular accumulation and secretion of Aβ42 oligomers. Moreover, Aβ40 activated the NF-κB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile of gene expression. As inhibitors of the NF-κB pathway, we tested the capability of a double-stranded κB decoy oligonucleotide, the anti-inflammatory drug aspirin and the selective IκB kinase 2 inhibitor, AS602868, to modify the Aβ40-mediated effects. These treatments, transiently applied before Aβ exposure, completely inhibited p50/p65 nuclear translocation and neuronal damage. The κB decoy also inhibited the Aβ-induced release of cytochrome c, restored the levels of Bcl-XL, and prevented intraneuronal accumulation and secretion of Aβ42. These results open up interesting perspectives on the development of novel strategies targeting out NF-κB p50/p65 dimers for pharmacological intervention in AD.
SK-PC-B70M confers anti-oxidant activity and reduces Aβ levels in the brain of Tg2576 mice
Brain Research, 2009
B70M is an oleanolic-glycoside saponin-enriched fraction derived from the root of Pulsatilla koreana. Recently, it was reported that hederacolchiside-E is an active ingredient of SK-PC-B70M that confers a neuroprotective effect against the cytotoxicity induced by Aβ(1-42) in SK-N-SH neuroblastoma cells. SK-PC-B70M improves scopolamine-induced impairments of spatial working memory in rats. In the present study, we investigated whether SK-PC-B70M has a beneficial effect on the Tg2576 murine model of Alzheimer's disease. ELISA analysis revealed that the levels of soluble and insoluble forms of Aβ(1-42) in Tg2576 mice fed SK-PC-B70M (2000 ppm) from 11 months to 16 months of age were reduced to, respectively, 66% and 79% of the control Tg2576 mice. Anti-Aβ antibody-stained brain sections of Tg2576 mice with SK-PC-B70M (2000 ppm) consistently showed a reduction in plaque formation in the brain. Western blot analyses showed altered expressions of various cellular factors, such as up-regulation of transthyretin, phospho-ERK, and phospho-CREB in the brain treated with SK-PC-B70M. SK-PC-B70M suppressed the neuronal toxicity induced by H 2 O 2 in primary cortical culture. Moreover, biochemical and immunohistochemical analyses showed that the levels of malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), oxidized by-products of lipid peroxidation, were notably reduced in the hippocampus of Tg2576 mice treated with SK-PC-B70M compared with the Tg2576 control. These results suggest that SK-PC-B70M attenuates AD-like pathology in the brain of Tg2576 mice.