中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 张继国
, ZHANG Jiguo
糖原合成酶激酶-3β(GSK-3β)为存在于真核细胞内的多功能丝氨酸/苏氨酸蛋白激酶,广泛表达于哺乳动物的肌肉、脂肪、肝脏和脑等组织中。GSK-3β在体内参与细胞分化、胚胎发育、炎症反应、细胞周期等多种病理生理过程。近年研究发现其通过调控Aβ异常聚集、tau蛋白磷酸化、神经细胞凋亡和炎症反应等参与阿尔茨海默病(AD)的发病过程。该文就GSK-3β在AD中的作用及可能的机制进行了综述。
Glycogen synthase kinase-3β (GSK-3β) as a multifunctional serine/threonine protein kinase is widely expressed in eukaryotic cells, such asin mammalian muscles, fat, liver, and brain.GSK-3β is involved in many pathophysiological processes such as cell differentiation, embryonic development, inflammatory response, and cell cycle
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糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)为丝氨酸/苏氨酸激酶,因磷酸化糖原合成酶而得名[1]。GSK-3β发挥生物学作用主要通过磷酸化调节、细胞内定位调节及结合蛋白的调节3种方式,其作用底物多达50多种,主要包括各种结构蛋白、调控代谢蛋白酶类以及转录因子,最常见的有微管相关蛋白Tau、β-连环蛋白(β-catenin)和环磷酸腺苷(cyclic adenosine monophosphate,cAMP)等[2]。GSK-3β的活性也受磷酸化调控,其氨基端的丝氨酸位点(Ser9)磷酸化后其活性受抑,蛋白激酶C(PKC)、蛋白激酶A(PKA)可磷酸化此位点抑制其活性;而酪氨酸位点(Thr216)磷酸化后可增强其活性[3]。中枢神经系统富集GSK-3β,其通过磷酸化代谢酶、信号蛋白、结构蛋白和转录因子参与各种神经元功能,与多种中枢神经系统疾病相关,如阿尔茨海默病(Alzheimer’s disease,AD)[4]。研究发现,GSK-3β可通过调控多条信号转导通路,参与与AD发生发展密切相关的β-淀粉样蛋白(amyloid protein β,Aβ)的生成、Tau 蛋白的磷酸化、神经元细胞的凋亡及炎症反应等病理过程,本文对此进行综述。
AD是痴呆的常见类型,随着人口老龄化,发病率逐年升高,越来越受到人们的关注。AD典型的神经病理学改变是:Aβ在脑内的沉积所形成的老年斑(senile plaques,SPs),Tau蛋白的过度磷酸化形成的神经原纤维缠结(neurofibrillary tangles,NFTs),神经元凋亡以及一系列的炎症反应。早在1997年研究发现,AD患者大脑中GSK-3β高表达,说明GSK-3β可能参与了AD的发病过程,其后人们对GSK-3β在AD中的作用及机制展开了深入的研究[5]。在动物及细胞实验中观察到了与AD患者相同的结果,也证实GSK-3β 的异常激活可以引起 Aβ生成增多、 tau 蛋白的过度磷酸化、诱导凋亡及参与炎症反应等,而其上述作用的发挥与其调控多条信号通路有关[6,7,8]。
PI3K/AKT/GSK-3β 由磷脂酰肌醇3-激酶(phoshoinositide 3-kinase,PI3K)、蛋白激酶B(protein kinase B,PKB,AKT),GSK-3β三个信号分子组成。正常情况下,活化的PI3K会在细胞膜产生3,4,5-三磷酸磷脂酰肌醇(phosphatidylinositol 3,4,5-trisphosphate,PIP3),即第二信使。PIP3与含有PH结构域(pleckstrin homology domain)的AKT相互作用,使AKT在磷酸肌醇依赖性激酶(phosphoinositi dedependent kinase,PDK)的作用下发生Ser308位点的磷酸化,进而活化AKT。GSK-3β可与活化的AKT结合,诱导GSK-3β向细胞膜转位,及GSK-3β氨基端的Ser9位点发生磷酸化,使之失活。
Wnt信号途径是由Wnt特异性跨膜受体卷曲蛋白(frrizled,Frz)、蓬乱蛋白(dishevelled,DSH)、 GSK-3β、轴蛋白(Axin)、大肠腺瘤样息肉基因(APC)、β-连环蛋白(β-catenin)、T细胞因子/淋巴样增强因子(Tc/fLef)及其他一些基因的表达产物共同构成[12]。β-catenin在Wnt信号通路活动完成过程中起关键作用,Wnt可与其膜受体的 Frz胞外N端具有富含半胱氨酸的结构域(cysteine rich domain,CRD)结合,这一作用可抑制DSH对β-catenin的降解,从而使β-catenin在细胞质中积累,而β-catenin可进入细胞核影响转录因子TCF/LEF,进而调节靶基因的表达。GSK-3β在β-catenin的降解中起关键作用,GSK-3β是DSH的下游分子,DSH激活可抑制GSK-3β的活化,而GSK-3β的失活可抑制β-catenin的磷酸化,保留其活性,因此GSK-3β是Wnt信号通路的重要分子。
Aβ级联假说认为Aβ是AD发病的关键分子,GSK-3β的活性增加可以促进Aβ的形成和异常聚集,而异常聚集的Aβ反过来也可以通过增加GSK-3β的活性,引起
Aβ由β-淀粉样蛋白前体蛋白(β-amyloid precursor protein,APP)水解而来,APP水解包括非淀粉样蛋白水解途径和淀粉样蛋白水解途径,其分解的关键酶分别为α,β和γ分泌酶。GSK-3β对APP及其分解过程的关键酶均具有调控作用。APP是GSK-3β的底物,其分解代谢受GSK-3β的调控,GSK-3β可使其分解更倾向于淀粉样蛋白水解途径,最终大量生成Aβ[19]。研究发现,GSK-3β还可以调控APP的表达水平,如GSK-3β与一种新的肽脯氨酰异构酶Pin1(protein interaction with NIMA1)结合并相互作用,抑制其生物活性后,可降低APP的表达水平[20]。在非淀粉样蛋白水解途径中,APP被α和γ分泌酶依次水解。GSK-3β可通过抑制金属蛋白酶(ADAM)的活性来下调α分泌酶复合物的活性,抑制APP的非淀粉样蛋白水解[21]。在淀粉样蛋白生成途径中,APP首先被β分泌酶切割,随后在γ分泌酶的作用下释放出Aβ40或Aβ42。β分泌酶是一种天冬氨酸酰蛋白酶,又名BACE1(β-site APP cleaving enzyme 1),其活性位点位于膜的内侧。抑制GSK-3β可通过NF-κB信号传导机制减少BACE1介导的APP剪切。Ly及其同事的研究结果表明抑制GSK-3β的活性可有效降低BACE1介导的APP蛋白的淀粉样蛋白水解途径作用,从而减少Aβ的生成、沉积以及神经炎性斑块的数量,最终可以增强转基因小鼠的学习和记忆能力[22]。γ分泌酶复合物由APH1(前咽缺陷蛋白-1)、PEN2(早老蛋白增强子-2)及Nicastrin(NCT)外,Presenilin蛋白(PS1和PS2)是催化的核心组成成分,而PS1是GSK-3β的底物,GSK-3β可通过PS1调控γ分泌酶的活性,从而促进Aβ的生成过程[23]。
NFTs是AD的另一个病理学特征,由过度磷酸化的Tau蛋白形成。正常生理状态下,Tau蛋白在蛋白激酶和蛋白磷酸化酶的共同调解下,处于磷酸化水平的动态平衡状态,从而维持正常的生理功能。在病理状态下,Tau蛋白的动态平衡被打破,导致Tau过度磷酸化,Tau过度磷酸化导致其从微管分离,聚合形成双螺旋纤维(paried helical filaments,PHF)最终形成NFTs。目前为止,已知的功能相关的磷酸化位点有丝氨酸和苏氨酸,这些位点的磷酸化与去磷酸化在AD中扮演了重要的角色。作为Tau蛋白高度磷酸化的上游信号分子,GSK-3β被认为是AD发生过程中Tau高度磷酸化的关键激酶[24],它可催化Tau蛋白上多个丝氨酸或苏氨酸位点的磷酸化[25]。研究发现在AD转基因小鼠实验中,在脑组织的NFTs中可以检测出较高的GSK-3β蛋白表达[26]。另有研究发现,Ⅰ型钙蛋白酶(Calpain Ⅰ)可以水解GSK-3β的C末端结构,导致GSK-3β的活性增强,从而引起Tau的过度磷酸化和AD的发生[27]。
细胞凋亡是AD脑内神经元的重要病理改变,有研究发现AD患者脑组织内存在较多TUNEL染色阳性的凋亡神经细胞,且主要为神经元细胞。GSK-3β可通过Wnt信号通路而调控神经细胞凋亡[28]。PI3K/AKT信号通路是细胞存活的重要通路之一,其中AKT/PKB、环磷酸腺苷反应元件结合蛋白(cAMP-response element binding protein,CREB)、NF-κB等是 PI3K/AKT信号通路中的重要分子,它们通过调节凋亡相关蛋白,如Bcl-2,Bax等因子的表达水平,实现对细胞生存的调节,其中磷酸化的AKT通过促进丝氨酸/苏氨酸残基底物磷酸化而发挥抗凋亡的作用。GSK-3β是PI3K/AKT信号通路的下游分子,通过Bcl-2家族抗凋亡蛋白Mcl-1(myeloid cell leukemia-1)磷酸化来诱导凋亡[29]。GSK-3β可以抑制促存活转录因子如热休克因子(heat shock factor 1,HSF1)、热休克蛋白70(heat shock protein,HSP70)、CREB及Bax凋亡基因,最后引起细胞凋亡[30]。由此可见,GSK-3β定在凋亡的信号转导途径中起着不可或缺的作用。
GSK-3β通过多条信号通路参与AD的发生与发展,因此将GSK-3β作为靶点来防治AD的研究越来越多,尤其是对GSK-3β抑制剂的研究。目前,已知的GSK-3β抑制剂主要有:靛玉红、锂、TDZD-8、SB415286、AR-A014418、L803-mts等。在APP转基因小鼠给予靛玉红和AR-A014418后,水迷宫实验表明二者可明显缓解APP转基因AD小鼠的记忆障碍,并且下调Tau蛋白的磷酸化[33]。而AD小鼠给与L803-mts和锂也得到了同样的结果[34,35]。氯化锂作为GSK-3β的抑制剂可以抑制IL-1β和TNF-α的释放,减轻炎症反应而保护AD[36]。细胞实验发现,迷迭香酸及其衍生物可通过作于 Akt/GSK-3β/Fyn通路减轻Aβ诱导的细胞氧化应激损伤[37,38]。
综上所述,GSK-3β通过多条信号通路调控Aβ的生成、Tau的磷酸化、细胞凋亡及炎症等而参与AD的病理学过程,而GSK-3β抑制剂能够逆转AD转基因动物的认知及病理变化,说明GSK-3β在AD发生发展中起着关键性的作用,因此以GSK-3β为靶点开发防治AD的药物具有重要的临床意义。
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Glycogen Synthase Kinase-3 (GSK-3) is a constitutively dynamic, omnipresent serine/threonine protein kinase regularly called as a
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Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism of cause and paucity of complete cure. Out of all the neurodegenerative diseases, Alzheimer's disease is the most devastating and loosening of thinking and judging ability disease that occurs in the old age people. Many hypotheses came forth in order to explain its causes. In this review, we have enlightened Glycogen Synthase Kinase-3 which has been considered as a concrete cause for Alzheimer's disease. Plaques and Tangles (abnormal structures) are the basic suspects in damaging and killing of nerve cells wherein Glycogen Synthase Kinase-3 has a key role in the formation of these fatal accumulations. Various Glycogen Synthase Kinase-3 inhibitors have been reported to reduce the amount of amyloid-beta as well as the tau hyperphosphorylation in both neuronal and nonneuronal cells. Additionally, Glycogen Synthase Kinase-3 inhibitors have been reported to enhance the adult hippocampal neurogenesis in vivo as well as in vitro. Keeping the chemotype of the reported Glycogen Synthase Kinase-3 inhibitors in consideration, they may be grouped into natural inhibitors, inorganic metal ions, organo-synthetic, and peptide like inhibitors. On the basis of their mode of binding to the constituent enzyme, they may also be grouped as ATP, nonATP, and allosteric binding sites competitive inhibitors. ATP competitive inhibitors were known earlier inhibitors but they lack efficient selectivity. This led to find the new ways for the enzyme inhibition.
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A number of studies have implicated a proline-directed protein kinase, glycogen synthase kinase-3 (GSK-3) in the hyperphosphorylation of tau in Alzheimer's disease (AD). Toward understanding the role of GSK-3 in the abnormal hyperphosphorylation of tau in AD we have found that GSK-3 is prominently present in neuronal cell bodies and their processes and co-localizes with neurofibrillary changes in AD brain. Furthermore, the levels of GSK-3 as determined by indirect ELISA are approximately 50% increased in the postsynaptosomal supernatant from AD brains as compared to the controls. However, no increase in GSK-3 enzyme activity was detected. In AD brain, with its reduced phosphatase activity, even normal levels of GSK-3 activity might be sufficient for the hyperphosphorylation of tau.
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Glycogen synthase kinase-3beta (GSK3beta) activity has been previously linked to Alzheimer's disease (AD) by its phosphorylation of tau and activation by amyloid. GSK3beta intracellular distribution is important in regulating its activity by restricting access to compartment-specific substrates. This study investigated regional and intracellular distribution of GSK3beta in a mouse model of AD, a bigenic mouse with combined amyloid and tau pathology (BiAT), and controls (FVB). At two different ages, the entire rostrocaudal extent of each brain was examined. Young (6-months-old) FVB and BiAT mice did not differ in GSK3beta expression and localization. In old (13-month-old) BiAT mice, neurons showed increased GSK3beta expression only in AD-relevant brain regions as compared with modest staining in region- and age-matched controls. Two regions with the most robust changes between FVB and BiAT mice, the amygdala and piriform cortex, were quantified at the light microscopic level. In both regions, the density of darkly labeled neurons was significantly greater in the old BiAT mice vs. the old FVB mice. Electron microscopy of the piriform cortex showed neuronal GSK3beta labeling in the rough endoplasmic reticulum, on ribosomes, and on microtubules in dendrites in both strains of mice. In old BiAT mice, GSK3beta labeling was qualitatively more robust compared to age-matched controls, and GSK3beta also appeared in neurofibrillary tangles. In conclusion, GSK3beta expression was increased in specific intracellular locations and was found in tangles in old BiAT mice, suggesting that GSK3beta overexpression in specific brain areas may be intrinsic to AD pathology.
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Alzheimer's disease (AD), a neurodegenerative disorder exhibiting progressive loss of memory and cognitive functions, is characterized by the presence of neuritic plaques composed of neurofibrillary tangles and beta-amyloid (All) peptide. Drug delivery to the brain still remains highly challenging for the treatment of AD. Several studies have been shown that curcumin is associated with anti-amyloidogenic properties, but therapeutic application of its beneficial effects is limited. Here we investigated possible mechanisms involved in curcumin protection against A beta(1-42)-induced cognitive impairment and, due to its poor bioavailability, we developed curcumin-loaded lipid-core nanocapsules in an attempt to improve the neuroprotective effect of this polyphenol. Animals received a single intracerebroventricular injection of A beta(1-42) and they were administered either free curcumin or curcumin-loaded lipid-core nanocapsules (CurLNC) intraperitoneally for 10 days. A beta(1-42)-infused animals showed a significant impairment on learning-memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels. Furthermore, animals exhibited activated astrocytes and microglial cells, as well as disturbance in BDNF expression and Akt/GSK-30 signaling pathway, beyond tau hyperphosphorylation. Our findings demonstrate that administration of curcumin was effective in preventing behavioral impairments, neuroinflammation, tau hyperphosphorylation as well as cell signaling disturbances triggered by A beta in vivo. Of high interest, Cur-LNC in a dose 20-fold lower presented similar neuroprotective results compared to the effective dose of free curcumin. Considered overall, the data suggest that curcumin is a potential therapeutic agent for neurocognition and nanoencapsulation of curcumin in LNC might constitute a promising therapeutic alternative in the treatment of neurodegenerative diseases such as AD. (C) 2013 Elsevier Inc.
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For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS).We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK) alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Abeta40/42 fragments, total and phosphorylated tau protein, and GSK-3alpha/beta were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Abeta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between Abeta42 and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.
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Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-beta peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3beta activity. GSK-3beta has been suggested to be a component of the gamma-secretase complex and is involved in amyloid-beta protein precursor processing. GSK-3beta along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target.
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Wnt signaling is a critical component during embryonic development and also plays an important role in regulating adult tissue homeostasis. Abnormal activation of Wnt signaling has been implicated in many cancers, while reduced activity of Wnt signaling leads to poor wound healing and structural formations. Thus, extensive efforts have been focused on developing small molecules that have potential to either inhibit or activate the pathway, hoping these molecules can offer leads for novel approaches in treating different human diseases. Many small-molecule inhibitors specifically target various elements, such as Frizzled, Disheveled, Porcupine, or Tankyrase, within the Wnt signaling pathways. These small molecules not only have the potential to be further developed as therapeutic reagents, but they may also be used as chemical probes to dissect the underlying mechanism of the Wnt signaling pathways. Therefore, their respective mechanisms and effective dosages are highly pertinent. Aiming to provide an overview of those molecules in a concise, easy-to-use manner, we summarize and organize the current research on them so that it may be helpful for utilization in different studies.
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Expression of the Wnt antagonist Dickkopf-1 (DKK1) is induced during neurodegenerative processes associated with Alzheimer's Disease and brain ischemia. However, little is known about DKK1-mediated effects on neurons. We now describe that, in cultured neurons, DKK1 is able to inhibit canonical Wnt signaling, as assessed by TCF reporter assay and analysis of beta-catenin levels, and to elicit cell death associated with loss of BCL-2 expression, induction of BAX, and TAU hyperphosphorylation. Local infusion of DKK1 in rats caused neuronal cell death and astrocytosis in the CA1 region of the hippocampus and death of cholinergic neurons in the nucleus basalis magnocellularis. Both effects were reversed by systemic administration of lithium ions, which rescue the Wnt pathway by inhibiting glycogen synthase kinase-3beta. The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hypothesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.
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Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.
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Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer disease (AD), and is associated with an increased risk of AD. Many studies have shown that apolipoprotein E epsilon 4 (APOE epsilon4) genotype is a major genetic predictor of AD progression, especially in patients with aMCI. However, the application of APOE genotyping in the diagnosis of MCI progressing to AD is limited by its low sensitivity and specificity, which often leads to high false-positive rate. The aim of this study was to evaluate serum brain-derived neurotrophic factor (BDNF) and hippocampal volume as predictors of aMCI to AD transition in APOE epsilon4 genotype patients.A total of 178 subjects were diagnosed with aMCI. The patients with aMCI that progressed to AD within 2 years were included in the MCI-AD group (n = 86), those maintaining an aMCI diagnosis after 2 years were placed in the MCI-MCI group (n = 92), and neurologically healthy age-matched individuals were set as controls (n = 90). APOE genotypes were determined. Blood samples from all subjects were drawn at baseline, 12 months, and 24 months for serum BNDF assessments. Hippocampal delineations were monitored by magnetic resonance imaging.Compared to control group, aMCI-AD patients (the patients with aMCI that progressed to AD within 2 years) exhibited worse performance on cognitive and neuropsychological batteries. Meanwhile, we found that aMCI-AD patients were associated with abnormally low serum BDNF level and greater hippocampal volume loss than MCI-MCI patients (patients maintaining an aMCI diagnosis after 2 years). Moreover, patients with aMCI who were carriers of APOE epsilon4 showed a notable decrease in serum BDNF and a significant reduction in hippocampal volume, especially in those who progressed to AD.The present study demonstrates that aMCI that evolves into AD in patients with the APOE epsilon4 genotype may be predicted by hippocampal volume and serum BDNF.
[本文引用:1]
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| [17] |
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| [18] |
Accumulating evidence suggests that glycogen synthase kinase 3 (GSK-3) is a multifunctional kinase implicated in Alzheimer's disease (AD). However, the synaptic actions of GSK-3 in AD conditions are largely unknown. In this study, we examined the impact of GSK-3 on N-methyl-D-aspartate receptor (NMDAR) channels, the major mediator of synaptic plasticity. Application of GSK-3 inhibitors or knockdown of GSK-3 caused a significant reduction of NMDAR-mediated ionic and synaptic current in cortical neurons, whereas this effect of GSK-3 was impaired in cortical neurons treated with beta-amyloid (A beta) or from transgenic mice overexpressing mutant amyloid precursor protein. GSK-3 activity was elevated by A beta, and GSK-3 inhibitors failed to decrease the surface expression of NMDA receptor NR1 (NR1) and NR1/postsynaptic density-95 (PSD-95) interaction in amyloid precursor protein mice, which was associated with the diminished GSK-3 regulation of Rab5 activity that mediates NMDAR internalization. Consequently, GSK-3 inhibitor lost the capability of protecting neurons against N-methyl-D-aspartate-induced excitotoxicity in A beta-treated neurons. These results have provided a novel mechanism underlying the involvement of GSK-3 in AD. Published by Elsevier Inc.
[本文引用:1]
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| [19] |
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| [20] |
Alzheimer disease (AD) is characterized by the presence of senile plaques of amyloid-beta (Abeta) peptides derived from amyloid precursor protein (APP) and neurofibrillary tangles made of hyperphosphorylated Tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether and how protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase kinase-3beta (GSK3beta) have been shown to have the opposite effects on APP processing and Tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3beta to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3beta activity. A point mutation either at Thr-330, the Pin1-binding site in GSK3beta, or at Thr-668, the GSK3beta phosphorylation site in APP, abolished the regulation of GSK3beta activity, Thr-668 phosphorylation, and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3beta kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer disease.
[本文引用:1]
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| [21] |
Amyloid beta (Abeta) plaques are pathological hallmarks of neurodegenerative Alzheimer's disease (AD) that is predominantly characterized by clinical symptoms of dementia. Therapies targeting Abeta are essential for preventing and treating AD. This review focuses on the non-amyloidogenic pathways that prevent the generation of Abeta peptide and thereby plaque formation in AD. An a-secretase-dependent cleavage of Amyloid Precursor Protein (APP) precludes the amyloidogenic pathway of Abeta generation. This non-amyloidogenic a-secretase activation thereby secretes sAPPa with prominent neurotrophic and memory-enhancing properties. Several
[本文引用:1]
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| [22] |
Deposition of amyloid beta protein (A beta) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). A beta is generated from sequential cleavages of the beta-amyloid precursor protein (APP) by the beta- and gamma-secretases, and beta-site APP-cleaving enzyme 1 (BACE1) is the beta-secretase essential for A beta generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating gamma-secretase activity, thereby facilitating A beta production. There are two highly conserved isoforms of GSK3: GSK3 alpha and GSK3 beta. We now report that specific inhibition of GSK3 beta, but not GSK3 alpha, reduced BACE1-mediated cleavage of APP and A beta production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3 beta was dependent on NF-kappa B signaling. Inhibition of GSK3 signaling markedly reduced A beta deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3 beta and that inhibition of GSK3 signaling can reduce A beta neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the beta-isoform of GSK3 may be a safe and effective approach for treating AD.
DOI:10.1172/JCI64516
URL
[本文引用:1]
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| [23] |
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| [24] |
Glycogen synthase kinase-3beta (GSK-3beta) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCepsilon activated Akt and inactivated GSK-3beta by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3beta. Combination of PKCepsilon activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3beta than each independent treatment, to suppress amyloid beta (Abeta)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.
[本文引用:1]
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| [25] |
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| [26] |
Glycogen synthase kinase-3beta (GSK3beta) activity has been previously linked to Alzheimer's disease (AD) by its phosphorylation of tau and activation by amyloid. GSK3beta intracellular distribution is important in regulating its activity by restricting access to compartment-specific substrates. This study investigated regional and intracellular distribution of GSK3beta in a mouse model of AD, a bigenic mouse with combined amyloid and tau pathology (BiAT), and controls (FVB). At two different ages, the entire rostrocaudal extent of each brain was examined. Young (6-months-old) FVB and BiAT mice did not differ in GSK3beta expression and localization. In old (13-month-old) BiAT mice, neurons showed increased GSK3beta expression only in AD-relevant brain regions as compared with modest staining in region- and age-matched controls. Two regions with the most robust changes between FVB and BiAT mice, the amygdala and piriform cortex, were quantified at the light microscopic level. In both regions, the density of darkly labeled neurons was significantly greater in the old BiAT mice vs. the old FVB mice. Electron microscopy of the piriform cortex showed neuronal GSK3beta labeling in the rough endoplasmic reticulum, on ribosomes, and on microtubules in dendrites in both strains of mice. In old BiAT mice, GSK3beta labeling was qualitatively more robust compared to age-matched controls, and GSK3beta also appeared in neurofibrillary tangles. In conclusion, GSK3beta expression was increased in specific intracellular locations and was found in tangles in old BiAT mice, suggesting that GSK3beta overexpression in specific brain areas may be intrinsic to AD pathology.
[本文引用:1]
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| [27] |
Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3beta (GSK-3beta) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3beta involved in AD is unclear. In the present study, we found that GSK-3beta was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3beta was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3beta 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-3beta 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-3beta by Ca(2+)/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3beta and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.
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| [28] |
Fluoxetine (FLX) is one of the selective serotonin reuptake inhibitors (SSRIs) antidepressants, which could be used to relieve depression and anxiety among AD patients. This study was designed to search for new mechanisms by which fluoxetine could activate Wnt/beta-catenin signaling pathway and reduce amyloidosis in AD brain. Fluoxetine was administered via intragastric injection to APP/tau/PS1 mouse model of Alzheimer's disease (3xTg-AD) mice for 4 months. In the hippocampus of AD mouse model, there could be observed neuronal apoptosis, as well as an increase in Abeta (amyloid-beta) production. Moreover, there is a strong association between down-regulation of Wnt/beta-catenin signaling and the alteration of AD pathology. The activity of protein phosphatases of type 2A (PP2A) could be significantly enhanced by the treatment of fluoxetine. The activation of PP2A, caused by fluoxetine, could then play a positive role in raising the level of active beta-catenin, and deliver a negative impact in GSK3beta activity in the hippocampal tissue. Both the changes mentioned above would lead to the activation of Wnt/beta-catenin signaling. Meanwhile, fluoxetine treatment would reduce APP cleavage and Abeta generation. It could also prevent apoptosis in 3xTg-AD primary neuronal cell, and have protective effects on neuron synapse. These findings imply that Wnt/beta-catenin signaling could be a potential target outcome for AD prevention, and fluoxetine has the potential to be a promising drug in both AD prevention and treatment.
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| [29] |
Numerous studies reveal that phosphatidylinositol (PI) 3-kinase and Akt protein kinase are important mediators of cell survival. However, the survival-promoting mechanisms downstream of these enzymes remain uncharacterized. Glycogen synthase kinase-3 beta (GSK-3 beta), which is inhibited upon phosphorylation by Akt, was recently shown to function during cell death induced by PI 3-kinase inhibitors. In this study, we tested whether GSK-3 beta is critical for the death of sympathetic neurons caused by the withdrawal of their physiological survival factor, the nerve growth factor (NGF). Stimulation with NGF resulted in PI 3-kinase-dependent phosphorylation of GSK-3 beta and inhibition of its protein kinase activity, indicating that GSK-3 beta is targeted by PI 3-kinase/Akt in these neurons. Expression of the GSK-3 beta inhibitor Frat1, but not a mutant Frat1 protein that does not bind GSK-3 beta, rescued neurons from death caused by inhibiting PI 3-kinase. Similarly, expression of Frat1 or kinase-deficient GSK-3 beta reduced death caused by inhibiting Akt. In NGF-maintained neurons, overexpression of GSK-3 beta caused a small but significant decrease in survival. However, expression of neither Frat1, kinase-deficient GSK-3 beta, nor GSK-3-binding protein inhibited NGF withdrawal-induced death. Thus, although GSK-3 beta function is required for death caused by inactivation of PI 3-kinase and Akt, neuronal death caused by NGF withdrawal can proceed through GSK-3 beta-independent pathways.
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| [30] |
Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of beta-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin contribute to the anti-apoptotic effects of ghrelin.
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| [31] |
The cellular mechanisms that directly regulate the inflammatory response after Toll-like receptor (TLR) stimulation are unresolved at present. Here we report that glycogen synthase kinase 3 (GSK3) differentially regulates TLR-mediated production of pro- and anti-inflammatory cytokines. Stimulation of monocytes or peripheral blood mononuclear cells with TLR2, TLR4, TLR5 or TLR9 agonists induced substantial increases in interleukin 10 production while suppressing the release of proinflammatory cytokines after GSK3 inhibition. GSK3 regulated the inflammatory response by differentially affecting the nuclear amounts of transcription factors NF-kappaB subunit p65 and CREB interacting with the coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response.
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| [32] |
AbstractMicroglia play a prominent role in the brain's inflammatory response to injury or infection by migrating to affected locations, secreting inflammatory molecules, and phagocytosing damaged tissue. However, because severe or chronic neuroinflammation exacerbates many neurological conditions, controlling microglia actions may provide therapeutic benefits in a diverse array of diseases. Since glycogen synthase kinase-3 (GSK3) promotes inflammatory responses in peripheral immune cells, we investigated if inhibitors of GSK3 attenuated microglia responses to inflammatory stimuli. Treatment of BV-2 microglia with GSK3 inhibitors greatly reduced the migration of microglia in both a scratch assay and in a transwell migration assay. Treatment of BV-2 microglia with lipopolysaccharide (LPS) stimulated the production of interleukin-6 and increased the expression of inducible nitric oxide synthase (iNOS) and NO production. Each of these microglia responses to inflammatory stimulation were greatly attenuated by GSK3 inhibitors. However, GSK3 inhibitors did not cause a general impairment of microglia functions, as the LPS-induced stimulated expression of cylcooxygenase-2 was unaltered. Regulation of microglia functions were also evident in cultured mouse hippocampal slices where GSK3 inhibitors reduced cytokine production and microglial migration, and provided protection from inflammation-induced neuronal toxicity. These findings demonstrate that GSK3 promotes microglial responses to inflammation and that the utilization of GSK3 inhibitors provides a means to limit the inflammatory actions of microglia. |
| [33] |
AbstractIndirubin and its derivatives have been shown to possess potent inhibitory effects on cyclin-dependent protein kinase 5 and glycogen synthase kinase 3β, two protein kinases involved in abnormal hyperphosphorylation of tau and amyloid precursor protein processing/β-amyloid (Aβ) production. Here, we showed that systemic treatment of APP and presenilin 1 (PS1) transgenic mice, a robust Alzheimer's disease (AD) mouse model, with indirubin-3'-monoxime (IMX; 20 mg/kg; 3 times weekly), for as little as 2 months, significantly attenuated spatial memory deficits. This was accompanied by a marked decrease in several AD-like phenotypes, including Aβ deposition, tau hyperphosphorylation, accumulation of activated microglia and astrocytes around Aβ plaques, and loss of synaptophysin immunoreactivity. These findings suggest that IMX is a potential therapeutic agent to combat AD. |
| [34] |
Accumulation of beta-amyloid (Abeta) deposits is a primary pathological feature of Alzheimer disease that is correlated with neurotoxicity and cognitive decline. The role of glycogen synthase kinase-3 (GSK-3) in Alzheimer disease pathogenesis has been debated. To study the role of GSK-3 in Abeta pathology, we used 5XFAD mice co-expressing mutated amyloid precursor protein and presenilin-1 that develop massive cerebral Abeta loads. Both GSK-3 isozymes (alpha/beta) were hyperactive in this model. Nasal treatment of 5XFAD mice with a novel substrate competitive GSK-3 inhibitor, L803-mts, reduced Abeta deposits and ameliorated cognitive deficits. Analyses of 5XFAD hemi-brain samples indicated that L803-mts restored the activity of mammalian target of rapamycin (mTOR) and inhibited autophagy. Lysosomal acidification was impaired in the 5XFAD brains as indicated by reduced cathepsin D activity and decreased N-glycoyslation of the vacuolar ATPase subunit V0a1, a modification required for lysosomal acidification. Treatment with L803-mts restored lysosomal acidification in 5XFAD brains. Studies in SH-SY5Y cells confirmed that GSK-3alpha and GSK-3beta impair lysosomal acidification and that treatment with L803-mts enhanced the acidic lysosomal pool as demonstrated in LysoTracker Red-stained cells. Furthermore, L803-mts restored impaired lysosomal acidification caused by dysfunctional presenilin-1. We provide evidence that mTOR is a target activated by GSK-3 but inhibited by impaired lysosomal acidification and elevation in amyloid precursor protein/Abeta loads. Taken together, our data indicate that GSK-3 is a player in Abeta pathology. Inhibition of GSK-3 restores lysosomal acidification that in turn enables clearance of Abeta burdens and reactivation of mTOR. These changes facilitate amelioration in cognitive function.
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| [35] |
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| [36] |
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Oxidative stress is an important pathogenic factor in Alzheimer's disease (AD). Recently, nuclear factor E2-related factor 2 (Nrf2) has emerged as a master regulator for the endogenous antioxidant response, and thus represents an attractive therapeutic target against AD. The aim of this study is to test the hypothesis that rosmarinic acid (RosA) attenuates amyloid-beta (Abeta)-evoked oxidative stress through activating Nrf2-inducible cellular antioxidant defense system. Here, we reported that RosA attenuated Abeta-induced cellular reactive oxygen species (ROS) generation and lipid hydroperoxides (LPO). Interestingly, knockdown of Nrf2 by plasmid-based short hairpin RNA (shRNA) abrogated, at least in part, RosA-mediated neuroprotection in Abeta-challenged PC12 cells. Mechanistically, RosA enhanced the nuclear translocation of Nrf2 and binding to antioxidant response element (ARE) core element but did not induced Nrf2 transcription. Simultaneously, RosA induced a set of Nrf2 downstream target genes encoding phase-II antioxidant enzymes. Furthermore, RosA enhanced protein kinase B (Akt) phosphorylation, glycogen synthase kinase-3beta (GSK-3beta) phosphorylation at Ser9, and Fyn phosphorylation. Noteworthy, pharmacological inhibition or gene knockdown studies demonstrated that Akt locate upstream of GSK-3beta and regulate Nrf2 through Fyn in the context of PC12 cells pre-incubated with RosA following exposed to Abeta. Conversely, the antioxidant effects of RosA could be blocked by Akt inhibitors LY294002, GSK-3beta inhibitor LiCl, Nrf2 shRNA, or Fyn shRNA in Abeta-challenged PC12 cells. Consequently, the antioxidant effects of RosA are mediated predominantly by Akt/GSK-3beta/Fyn pathway through increased activity of Nrf2. These results suggest, although do not prove, that RosA can be a promising candidate for neuroprotective treatment of AD.
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| [38] |
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