The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jianzhi Wang - One of the best experts on this subject based on the ideXlab platform.
-
betaine attenuates alzheimer like pathological changes and memory deficits induced by homocysteine
Journal of Neurochemistry, 2013Co-Authors: Gaoshang Chai, Jianzhi Wang, Qun Wang, Aoji Xie, Xia Jiang, Xiangshu Cheng, Gongping LiuAbstract:Hyperhomocysteinemia (Hhcy) may induce memory deficits with β-amyloid (Aβ) accumulation and tau Hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau Hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau Hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2AC at Leu309 and phosphorylated PP2AC at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.
-
synaptic released zinc promotes tau Hyperphosphorylation by inhibition of protein phosphatase 2a pp2a
Journal of Biological Chemistry, 2012Co-Authors: Xuying Sun, Qun Wang, Xiaochuan Wang, Yuping Wei, Yan Xiong, Aoji Xie, Xiulian Wang, Yang Yang, Rong Liu, Jianzhi WangAbstract:Abstract Hyperphosphorylated tau is the major component of neurofibrillary tangles in Alzheimer disease (AD), and the tangle distribution largely overlaps with zinc-containing glutamatergic neurons, suggesting that zinc released in synaptic terminals may play a role in tau phosphorylation. To explore this possibility, we treated cultured hippocampal slices or primary neurons with glutamate or Bic/4-AP to increase the synaptic activity with or without pretreatment of zinc chelators, and then detected the phosphorylation levels of tau. We found that glutamate or Bic/4-AP treatment caused tau Hyperphosphorylation at multiple AD-related sites, including Ser-396, Ser-404, Thr-231, and Thr-205, while application of intracellular or extracellular zinc chelators, or blockade of zinc release by extracellular calcium omission almost abolished the synaptic activity-associated tau Hyperphosphorylation. The zinc release and translocation of excitatory synapses in the hippocampus were detected, and zinc-induced tau Hyperphosphorylation was also observed in cultured brain slices incubated with exogenously supplemented zinc. Tau Hyperphosphorylation induced by synaptic activity was strongly associated with inactivation of protein phosphatase 2A (PP2A), and this inactivation can be reversed by pretreatment of zinc chelator. Together, these results suggest that synaptically released zinc promotes tau Hyperphosphorylation through PP2A inhibition.
-
dehydroevodiamine attenuates calyculin a induced tau hyperphos phorylation in rat brain slices
Acta Pharmacologica Sinica, 2007Co-Authors: Jiang Fang, Shao-hui Wang, Qing Tian, Xiao-ping Hong, Jianzhi WangAbstract:This study was to investigate the effect of dehydroevodiamine (DHED) on Alzheimer's disease (AD)-like tau Hyperphosphorylation induced by calyculin A (CA), an inhibitor of protein phosphatase (PP)-2A and PP-1, and the involvement of PP-2A in metabolically competent rat brain slices. Rat brain slices were pre-incubated at 33°C in the presence (10, 100, and 200 μmol/L, respectively) or absence of DHED for 1 h. Then, CA 0.1 μmol/L was added and the slices were treated for another 2 h. Western blotting and/or immunohistochemistry were used to measure the phosphorylation level of tau and PP-2A. CA treatment could remarkably increase the immunoreactivity of pS262 and decrease the staining of Tau-1, representing tau Hyperphosphorylation at Ser262 (pS262) and Ser198/ 199/202 (Tau-1, as the antibody reacts with unphosphorylated tau, therefore, decreased staining represents increased phosphorylation). Pre-incubation of the brain slices with DHED could efficiently attenuate the CA-induced tau Hyperphosphorylation at the above AD-related sites. Additionally, DHED also decreased the basal phosphorylation level of tau at Ser396, although CA failed to induce tau Hyperphosphorylation at this site. Furthermore, CA treatment induced an increased level of Tyr307-phosphorylated PP-2A, which represents inactivation of the phosphatase, whereas DHED arrested the elevation of the inhibitory modification of PP-2A. DHED can attenuate CA-induced tau Hyperphosphorylation at multiple AD-related sites in metabolically active rat brain slices. The underlying mechanism may involve a decreased inhibitory phosphorylation of PP-2A at Tyr307.
-
effect of melatonin on calyculin a induced tau Hyperphosphorylation
European Journal of Pharmacology, 2005Co-Authors: Xiachun Li, Zefen Wang, Junxia Zhang, Qun Wang, Jianzhi WangAbstract:Abstract We have found in the present study that incubation of neuroblastma N2a with calyculin A, an inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1), reduces cell viability in a dose-dependent manner, and leads to tau Hyperphosphorylation at tau-1 (Ser198/199/202) and PHF-1 (Ser396/404) epitopes. In addition to inhibit PP-2A, calyculin A treatment also results in significant activation of glycogen synthase kinase-3 (GSK-3). Calyculin A induces oxidative stress manifested by elevated level of malondialdehyde and decreased activity of superoxide dismutase. When the cells were incubated simultaneously with calyculin A and melatonin (25 μM or 50 μM), the calyculin A-induced decrease in cell viability, tau Hyperphosphorylation, PP-2A/GSK-3 imbalance and oxidative stress were attenuated accordingly. These results suggest (i) that calyculin A induces tau Hyperphosphorylation not only by inhibition of PP-2A, but also by activation of GSK-3 in N2a cells; (ii) that melatonin efficiently attenuates the calyculin A-induced damages through not only its antioxidant effect but also its modulation to the phosphorylation system.
-
overactivation of glycogen synthase kinase 3 by inhibition of phosphoinositol 3 kinase and protein kinase c leads to Hyperphosphorylation of tau and impairment of spatial memory
Journal of Neurochemistry, 2003Co-Authors: Shijie Liu, Qun Wang, Ai Hong Zhang, Heng Mei Deng, William J Netzer, Jianzhi WangAbstract:Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau Hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, Hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents Hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau Hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
Khalid Iqbal - One of the best experts on this subject based on the ideXlab platform.
-
truncation and activation of gsk 3β by calpain i a molecular mechanism links to tau Hyperphosphorylation in alzheimer s disease
Scientific Reports, 2015Co-Authors: Nana Jin, Cheng-xin Gong, Xiaomin Yin, Maohong Cao, Khalid Iqbal, Fei Ding, Fei LiuAbstract:Abnormal Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3β (GSK-3β) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3β involved in AD is unclear. In the present study, we found that GSK-3β was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3β was positively correlated with tau Hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3β in vitro at C-terminus, leading to an increase of its kinase activity, but keeping its characteristic to preferentially phosphorylate the protein kinase A-primed tau. Excitotoxicity induced by kainic acid (KA) caused GSK-3β truncation at C-terminus and Hyperphosphorylation of tau in mouse brain. Inhibition of calpain prevented the KA-induced changes. These findings suggest that truncation of GSK-3β by Ca2+/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3β and consequent abnormal Hyperphosphorylation of tau and neurofibrillary degeneration in AD.
-
cytoplasmic retention of protein phosphatase 2a inhibitor 2 i2pp2a induces alzheimer like abnormal Hyperphosphorylation of tau
Journal of Biological Chemistry, 2014Co-Authors: Mohammad Arif, Fei Liu, Gustavo Basurtoislas, Inge Grundkeiqbal, Jianshe Wei, Qi Zhang, Khalid IqbalAbstract:Abnormal Hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of Tau is regulated by protein phosphatase 2A (PP2A), which in turn is modulated by endogenous inhibitor 2 (I2PP2A). In AD brain, I2PP2A is translocated from neuronal nucleus to cytoplasm, where it inhibits PP2A activity and promotes abnormal phosphorylation of Tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2PP2A containing a conserved basic motif, 179RKR181, which is sufficient for directing its nuclear localization. The current study further presents an inducible cell model (Tet-Off system) of AD-type abnormal Hyperphosphorylation of Tau by expressing I2PP2A in which the NLS was inactivated by 179RKR181 → AAA along with 168KR169 → AA mutations. In this model, the mutant NLS (mNLS)-I2PP2A (I2PP2AAA-AAA) was retained in the cell cytoplasm, where it physically interacted with PP2A and inhibited its activity. Inhibition of PP2A was associated with the abnormal Hyperphosphorylation of Tau, which resulted in microtubule network instability and neurite outgrowth impairment. Expression of mNLS-I2PP2A activated CAMKII and GSK-3β, which are Tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2PP2A with PP2A and GSK-3β but not with CAMKII. Thus, the cell model provides insights into the nature of the potential NLS and the mechanistic relationship between I2PP2A-induced inhibition of PP2A and Hyperphosphorylation of Tau that can be utilized to develop drugs preventing Tau pathology.
-
activation of asparaginyl endopeptidase leads to tau Hyperphosphorylation in alzheimer disease
Journal of Biological Chemistry, 2013Co-Authors: Gustavo Basurtoislas, Fei Liu, Inge Grundkeiqbal, Yunn Chyn Tung, Khalid IqbalAbstract:Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2PP2A. In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2PP2A is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2PP2A translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2PP2A, except when I2PP2A was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2PP2A, inhibition of protein phosphatase 2A, and Hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2PP2A-protein phosphatase 2A-Tau Hyperphosphorylation pathway as a therapeutic target. Background: Abnormal Hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease. Results: Acidosis of the brain activates and translocates asparaginyl endopeptidase from neuronal lysosomes to the cytoplasm where it leads to Tau Hyperphosphorylation by inhibition of protein phosphatase 2A through cleavage of its inhibitor 2 into two active fragments. Conclusion: Activated asparaginyl endopeptidase causes Tau pathology. Significance: Brain acidosis can trigger Tau Hyperphosphorylation.
-
Hyperphosphorylation of microtubule associated protein tau a promising therapeutic target for alzheimer disease
Current Medicinal Chemistry, 2008Co-Authors: Cheng-xin Gong, Khalid IqbalAbstract:Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal Hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal Hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau Hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.
-
decreased glucose transporters correlate to abnormal Hyperphosphorylation of tau in alzheimer disease
FEBS Letters, 2008Co-Authors: Ying Liu, Fei Liu, Khalid Iqbal, Inge Grundkeiqbal, Cheng-xin GongAbstract:Brain glucose uptake/metabolism is impaired in Alzheimer disease (AD). Here, we report that levels of the two major brain glucose transporters (GLUT1 and GLUT3) responsible for glucose uptake into neurons were decreased in AD brain. This decrease correlated to the decrease in O-GlcNAcylation, to the Hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. We also found down-regulation of hypoxia-inducible factor 1, a major regulator of GLUT1 and GLUT3, in AD brain. These studies provide a possible mechanism by which GLUT1 and GLUT3 deficiency could cause impaired brain glucose uptake/metabolism and contribute to neurodegeneration via down-regulation of O-GlcNAcylation and Hyperphosphorylation of tau in AD.
Qun Wang - One of the best experts on this subject based on the ideXlab platform.
-
betaine attenuates alzheimer like pathological changes and memory deficits induced by homocysteine
Journal of Neurochemistry, 2013Co-Authors: Gaoshang Chai, Jianzhi Wang, Qun Wang, Aoji Xie, Xia Jiang, Xiangshu Cheng, Gongping LiuAbstract:Hyperhomocysteinemia (Hhcy) may induce memory deficits with β-amyloid (Aβ) accumulation and tau Hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau Hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau Hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2AC at Leu309 and phosphorylated PP2AC at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.
-
synaptic released zinc promotes tau Hyperphosphorylation by inhibition of protein phosphatase 2a pp2a
Journal of Biological Chemistry, 2012Co-Authors: Xuying Sun, Qun Wang, Xiaochuan Wang, Yuping Wei, Yan Xiong, Aoji Xie, Xiulian Wang, Yang Yang, Rong Liu, Jianzhi WangAbstract:Abstract Hyperphosphorylated tau is the major component of neurofibrillary tangles in Alzheimer disease (AD), and the tangle distribution largely overlaps with zinc-containing glutamatergic neurons, suggesting that zinc released in synaptic terminals may play a role in tau phosphorylation. To explore this possibility, we treated cultured hippocampal slices or primary neurons with glutamate or Bic/4-AP to increase the synaptic activity with or without pretreatment of zinc chelators, and then detected the phosphorylation levels of tau. We found that glutamate or Bic/4-AP treatment caused tau Hyperphosphorylation at multiple AD-related sites, including Ser-396, Ser-404, Thr-231, and Thr-205, while application of intracellular or extracellular zinc chelators, or blockade of zinc release by extracellular calcium omission almost abolished the synaptic activity-associated tau Hyperphosphorylation. The zinc release and translocation of excitatory synapses in the hippocampus were detected, and zinc-induced tau Hyperphosphorylation was also observed in cultured brain slices incubated with exogenously supplemented zinc. Tau Hyperphosphorylation induced by synaptic activity was strongly associated with inactivation of protein phosphatase 2A (PP2A), and this inactivation can be reversed by pretreatment of zinc chelator. Together, these results suggest that synaptically released zinc promotes tau Hyperphosphorylation through PP2A inhibition.
-
effect of melatonin on calyculin a induced tau Hyperphosphorylation
European Journal of Pharmacology, 2005Co-Authors: Xiachun Li, Zefen Wang, Junxia Zhang, Qun Wang, Jianzhi WangAbstract:Abstract We have found in the present study that incubation of neuroblastma N2a with calyculin A, an inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1), reduces cell viability in a dose-dependent manner, and leads to tau Hyperphosphorylation at tau-1 (Ser198/199/202) and PHF-1 (Ser396/404) epitopes. In addition to inhibit PP-2A, calyculin A treatment also results in significant activation of glycogen synthase kinase-3 (GSK-3). Calyculin A induces oxidative stress manifested by elevated level of malondialdehyde and decreased activity of superoxide dismutase. When the cells were incubated simultaneously with calyculin A and melatonin (25 μM or 50 μM), the calyculin A-induced decrease in cell viability, tau Hyperphosphorylation, PP-2A/GSK-3 imbalance and oxidative stress were attenuated accordingly. These results suggest (i) that calyculin A induces tau Hyperphosphorylation not only by inhibition of PP-2A, but also by activation of GSK-3 in N2a cells; (ii) that melatonin efficiently attenuates the calyculin A-induced damages through not only its antioxidant effect but also its modulation to the phosphorylation system.
-
injection of okadaic acid into the meynert nucleus basalis of rat brain induces decreased acetylcholine level and spatial memory deficit
Neuroscience, 2004Co-Authors: Qing Tian, Qun Wang, C X Gong, Xiulian Wang, Z Q Lin, Jiachun Chen, Junhan WangAbstract:Abnormal Hyperphosphorylation of tau and cholinergic deficit occur in the early stage of Alzheimer's disease (AD) and relate to the dementia symptom. Hyperphosphorylation of tau, neurofilament (NF) and other proteins in AD brain appears to be caused by a down-regulation of protein phosphatase 2A (PP2A), but the mechanism leading to cholinergic deficit is still unknown. In this study, we selectively inhibited PP2A by injection of okadaic acid (OA) into the Meynert nucleus basalis of rats. We found that injection of OA induced Hyperphosphorylation of tau and NF and decreased acetylcholine (ACh) level in the nucleus basalis of Meynert. These alterations were accompanied by spatial memory deficit in OA-injected rats. We also demonstrated that the OA-induced ACh reduction may be due to a failure of intraneuronal transport of choline acetyltransferase (ChAT) from cell body to the neuronal terminals rather than an alteration of activity of ChAT or acetylcholinesterase. This study suggests that a down-regulation of PP2A may underlie both abnormal Hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration and cholinergic deficiency in AD.
-
overactivation of glycogen synthase kinase 3 by inhibition of phosphoinositol 3 kinase and protein kinase c leads to Hyperphosphorylation of tau and impairment of spatial memory
Journal of Neurochemistry, 2003Co-Authors: Shijie Liu, Qun Wang, Ai Hong Zhang, Heng Mei Deng, William J Netzer, Jianzhi WangAbstract:Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau Hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, Hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents Hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau Hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
Cheng-xin Gong - One of the best experts on this subject based on the ideXlab platform.
-
truncation and activation of gsk 3β by calpain i a molecular mechanism links to tau Hyperphosphorylation in alzheimer s disease
Scientific Reports, 2015Co-Authors: Nana Jin, Cheng-xin Gong, Xiaomin Yin, Maohong Cao, Khalid Iqbal, Fei Ding, Fei LiuAbstract:Abnormal Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3β (GSK-3β) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3β involved in AD is unclear. In the present study, we found that GSK-3β was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3β was positively correlated with tau Hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3β in vitro at C-terminus, leading to an increase of its kinase activity, but keeping its characteristic to preferentially phosphorylate the protein kinase A-primed tau. Excitotoxicity induced by kainic acid (KA) caused GSK-3β truncation at C-terminus and Hyperphosphorylation of tau in mouse brain. Inhibition of calpain prevented the KA-induced changes. These findings suggest that truncation of GSK-3β by Ca2+/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3β and consequent abnormal Hyperphosphorylation of tau and neurofibrillary degeneration in AD.
-
Intranasal insulin ameliorates tau Hyperphosphorylation in a rat model of type 2 diabetes.
Journal of Alzheimer's disease : JAD, 2012Co-Authors: Yan Yang, Yuping Wang, Teng Jiang, Muxun Zhang, Cheng-xin GongAbstract:Recent studies have demonstrated that insulin plays important roles in the brain, including regulation of glucose metabolism and modulation of learning and memory. We have found dysregulation of brain insulin signaling in both Alzheimer's disease (AD) and type 2 diabetes (T2D), which correlates to Hyperphosphorylation of tau, a key abnormal tau modification leading to neurofibrillary tangles. Here, we investigated tau phosphorylation and the two key components of the insulin signaling pathway, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β), in a rat model of T2D produced by a high protein, high glucose, and high fat diet followed by intraperitoneal injection of streptozocin. We found tau Hyperphosphorylation, decreased AKT activation, and GSK-3β over-activation in T2D rat brains. Intranasal insulin treatment for four weeks normalized AKT and GSK-3β, as well as reduced tau Hyperphosphorylation in T2D rat brains, whereas four-week treatments with subcutaneous insulin had minimal effects on brain GSK-3β and tau phosphorylation. These results suggest decreased brain insulin signaling and tau Hyperphosphorylation in the rat model of T2D and demonstrate the efficacy of intranasal insulin treatment to reverse these brain abnormalities. Our findings provide further mechanism by which T2D increases the risk for AD and also support the potential use of intranasal insulin for the treatment of AD.
-
Hyperphosphorylation of microtubule associated protein tau a promising therapeutic target for alzheimer disease
Current Medicinal Chemistry, 2008Co-Authors: Cheng-xin Gong, Khalid IqbalAbstract:Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal Hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal Hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau Hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.
-
decreased glucose transporters correlate to abnormal Hyperphosphorylation of tau in alzheimer disease
FEBS Letters, 2008Co-Authors: Ying Liu, Fei Liu, Khalid Iqbal, Inge Grundkeiqbal, Cheng-xin GongAbstract:Brain glucose uptake/metabolism is impaired in Alzheimer disease (AD). Here, we report that levels of the two major brain glucose transporters (GLUT1 and GLUT3) responsible for glucose uptake into neurons were decreased in AD brain. This decrease correlated to the decrease in O-GlcNAcylation, to the Hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. We also found down-regulation of hypoxia-inducible factor 1, a major regulator of GLUT1 and GLUT3, in AD brain. These studies provide a possible mechanism by which GLUT1 and GLUT3 deficiency could cause impaired brain glucose uptake/metabolism and contribute to neurodegeneration via down-regulation of O-GlcNAcylation and Hyperphosphorylation of tau in AD.
-
okadaic acid induced inhibition of protein phosphatase 2a produces activation of mitogen activated protein kinases erk1 2 mek1 2 and p70 s6 similar to that in alzheimer s disease
American Journal of Pathology, 2003Co-Authors: Cheng-xin Gong, Inge Grundkeiqbal, Wenlin An, Bengt Winblad, Richard F Cowburn, Khalid IqbalAbstract:In Alzheimer's disease (AD) brain the activity of protein phosphatase (PP)-2A is compromised and that of the extracellular signal-regulated protein kinase (ERK1/2) of the mitogen-activated protein kinase (MAPK) family, which can phosphorylate tau, is up-regulated. We investigated whether a decrease in PP-2A activity could underlie the activation of these kinases and the abnormal Hyperphosphorylation of tau. Rat brain slices, 400-μm-thick, kept under metabolically active conditions in oxygenated (95% O 2 , 5% CO 2 ) artificial CSF were treated with 1.0 μmol/L okadaic acid (OA) for 1 hour at 33°C. Under this condition, PP-2A activity was decreased to ∼35% of the vehicle-treated control slices, and activities of PP-1 and PP-2B were not affected. In the OA-treated slices, we observed a dramatic increase in the phosphorylation/activation of ERK1/2, MEK1/2, and p70 S6 kinase both immunohistochemically and by Western blots using phosphorylation-dependent antibodies against these kinases. Treatment of 6-μm sections of the OA-treated slices with purified PP-2A reversed the phosphorylation/activation of these kinases. Hyperphosphorylation of tau at several abnormal Hyperphosphorylation sites was also observed, as seen in AD brain. These results suggest 1) that PP-2A down-regulates ERK1/2, MEK1/2, and p70 S6 kinase activities through dephosphorylation at the serine/threonine residues of these kinases, and 2) that in AD brain the decrease in PP-2A activity could have caused the activation of ERK1/2, MEK1/2, and p70 S6 kinase, and the abnormal Hyperphosphorylation of tau both via an increase in its phosphorylation and a decrease in its dephosphorylation.
Huaqiao Wang - One of the best experts on this subject based on the ideXlab platform.
-
quercetin inhibits okadaic acid induced tau protein Hyperphosphorylation through the ca2 calpain p25 cdk5 pathway in ht22 cells
International Journal of Molecular Medicine, 2017Co-Authors: Xiu Yin Shen, Sheng Li, Ou Yang Ting, Feng He, Jie Xu, Huaqiao WangAbstract:: Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein Hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein Hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein Hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein Hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.
-
quercetin protects against okadaic acid induced injury via mapk and pi3k akt gsk3β signaling pathways in ht22 hippocampal neurons
PLOS ONE, 2016Co-Authors: Wei Jiang, Xiu Yin Shen, Sheng Li, Feng He, Jie Xu, Yue Zhou, Huaqiao WangAbstract:Increasing evidence shows that oxidative stress and the Hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer’s disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the Hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the Hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.