糖原合酶激酶3在阿尔茨海默病发病中的作用及干预措施探讨
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摘要
阿尔茨海默病是(Alzheimer’s disease, AD)一种高发于老年人群的痴呆,其主要病理改变为tau蛋白过度磷酸化组成的细胞内神经纤维原缠结,过量产生的Aβ组成的细胞外老年斑,大量营养不良性神经炎导致的神经元丢失。AD的主要临床特征是进行性记忆能力下降,研究表明,突触可塑性能力的下降是引起学习记忆能力下降的根本原因。
糖原合酶激酶3 (Glycogen synthase kinase-3, GSK-3)是一种在神经元的发育和成熟过程中非常重要的蛋白激酶,在引起AD样tau蛋白过度磷酸化,Aβ产生增加,导致AD样学习记忆障碍中起了重要作用,而对其引起AD样学习记忆障碍机制的研究尚缺乏。
我们在本研究中重点探讨了GSK-3在突触可塑性中的作用,重点探讨了在我们已经报道的具有AD样学习记忆障碍的动物模型上GSK-3对长时程增强(Long term potentiation, LTP)的影响并且从突触前递质释放,轴突运输,突触后形态改变,蛋白合成变化等方面探索了其内在机制。主要结果如下:
第一部分糖原合酶激酶3对突触可塑性的影响及其可能的机制
阿尔茨海默病(Alzheimer’s disease, AD)是最常见的高发于老龄人群中的痴呆疾病,激活GSK-3可以引起AD的记忆能力下降,但是其机制并不明了。我们在本研究中发现通过wortmannin和瞬时转染野生型GSK-3β(wt-GSK-3β)的质粒可以抑制大鼠海马长时程增强(long term potentiation, LTP)的诱导,而同时用锂剂或者SB216763亦或转染显性负突变GSK-3β(dn-GSK-3β)可以逆转该损伤。随着GSK-3的激活,与LTP相关的突触结构也同时受损,包括突触前活性区域减少,突触间隙变宽,突触后致密物质减少。在突触前水平,GSK-3激活时,谷氨酸释放和synapsin I(一种对调节突触释放十分重要的蛋白)在其含量和聚集上也发生了改变。我们还发现synapsin I的这种改变是不依赖于LTP的。突触后水平,我们发现PSD93和NR2A/B含量明显降低。我们认为,激活GSK-3不仅损伤突触的形态而且损伤其功能,这可能是其导致记忆损伤的机制。
第二部分糖原合酶激酶3激活阻碍钙依赖的胞吐及其机制
糖原合酶激酶3(GSK-3)在神经元的发育和成熟过程中发挥了重要的作用,而其在对神经元基本生理功能的研究尚缺乏。我们在本研究中发现,过度表达野生型GSK-3β可抑制海马神经元的胞吐现象,而且主要是通过抑制囊泡以完全融合方式的胞吐。我们还发现,激活GSK-3可降低钙离子内流以及与突触囊泡释放密切相关的Synaptophysin I/VAMP2 (囊泡相关膜蛋白2)复合体的解离障碍,激活GSK-3促进P/Q型钙通道突触结合位点的磷酸化。据此,我们推测GSK-3激活可能通过磷酸化突触前钙通道蛋白,降低钙内流,从而引发突触囊泡相关蛋白的功能紊乱,最终抑制神经元的胞吐作用。
第三部分糖原合酶激酶3激活对驱动蛋白轻链介导的VAMP2蛋白顺向轴突转运的抑制作用及其机制
糖原合酶激酶3(GSK-3)是一种在在神经元的发育和成熟过程中发挥了重要的作用的蛋白激酶,前期的报道显示激活GSK-3可以通过磷酸化驱动蛋白轻链蛋白(KLC)来负性调节轴突运输。我们的研究中发现,过度表达GSK-3可以使VAMP2蛋白的轴突转运受到阻抑,从而使到达轴突远端的VAMP2蛋白含量降低。我们还发现,GSK-3这种对轴突运输的阻抑作用可能是通过其对KLC的蛋白表达的抑制引起的。因此,我们推测GSK-3可能通过降低KLC的量进而阻滞其介导的顺向轴突转运。
第四部分雌激素对糖原合酶激酶3激活引起的tau蛋白过度磷酸化的保护作用
雌激素水平的降低与阿尔茨海默病(AD)的高发性密切相关。阿尔茨海默病(AD)是最常见的与年龄相关的痴呆病之一,其病理学特征为神经原纤维缠结(NFTs)和老年斑(SP)。过度磷酸化的微管相关蛋白和β样淀粉蛋白(Aβ)分别构成了神经纤维缠结和老年斑的主要成分。先前有研究表明雌激素能有效缓解Aβ引起的细胞毒性。然而,雌激素是否同样影响tau蛋白磷酸化?其潜在的机制又如何呢?在这篇文章中,我们给予wortmannin (Wort)和GF-109203X (GFX)处理neuro2A (N2a)细胞,以激活糖原合成激酶-3(GSK-3),诱导出tau蛋白过度磷酸化模型。在这个实验中,我们发现17β-雌二醇(βE2)能够缓解Wort/GFX-诱导的与众多AD-相关位点上的tau蛋白的过度磷酸化,如Ser396/404,Thr231,Thr205,Ser199/202。同时,βE2还能使非活性形式的GSK-3β(Ser9位磷酸化)增加。βE2对GSK-3β的作用通过瞬时过度表达GSK-3β得到确证。为了证明βE2对GSK-3β和tau蛋白磷酸化的保护作用是否通过GSK-3的上游因子之一----蛋白激酶B(Akt)?我们在N2a细胞上瞬时转染了显性负突变Akt质粒(dn-Akt)。结果显示,βE2对Wort/GFX-诱导的GSK-3β的激活和tau蛋白的过度磷酸化的缓解作用是不依赖于Akt的。这就提示βE2通过直接作用于GSK-3β来减少AD样tau蛋白的过度磷酸化。
Alzheimer’s disease (AD) is the most popular dementia in aged people. The main pathological hallmarks in AD are the formation of intracellular neurofibrillary tangles consisted of hyperphosphorylated tau, extracellular senile plaques consisted ofβ-amyloid (Aβ) peptide, neuronal loss caused by dystrophic neuritis. The main character of AD in clinical is progressive memory loss. Previously studies had revealed that the dysfunction of synaptic plasticity is the primary reason for learning/memory deficits in AD.
Glycogen synthase kinase-3 (GSK-3) is a crucial protein kinase which is necessary for the development and maturity of neuron. It is also known that GSK-3 plays an important role in the pathogenesis of AD, such as induces tau hyperphosphorylation, increases the production of Aβand leads to AD-like learning/memory deficits. However, the mechanisms of GSK-3 induce AD-like learning/memory deficits is still unknown.
In the present study, we aimed to investigate the role of GSK-3 in synaptic plasticity, especially on the effect of GSK-3 activation to LTP in our previously reported animal model with AD-like learning/memory deficits. We also explore the underlying mechanisms through the changing of presynaptic neurotransmitter releasing, axonal transport, morphological changes in post-synpase and protein synthesis. The main results are as following:
Part I Activation of glycogen synthase kinase-3 inhibits long term potentiation with synapse-associated impairments
Activation of glycogen synthase kinase-3 (GSK-3) can cause memory deficits as seen in Alzheimer’s disease (AD), the most common age-associated dementia, but the mechanism is not understood. Here, we found that activation of GSK-3 by wortmannin or transient overexpression of wild type GSK-3β(wt-GSK-3β) could suppress the induction of long term potentiation (LTP) in rat hippocampus, while simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant negative GSK-3βmutant (dn-GSK-3β) preserved the LTP. With activation of GSK-3, prominent LTP-associated synapse impairments including less presynaptic active zone, thinner postsynaptic density (PSD) and broader synaptic cleft were observed in the hippocampal slices after high frequency stimulation (HFS). In presynaptic level, the release of glutamate and the expression/clustering of synapsin I, a synaptic vesicle protein playing an important role in neurotransmitter release, decreased markedly upon upregulation of GSK-3. In vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of HFS. In postsynaptic level, the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was activated. These synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of dnGSK-3. We conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally, which may underlie the GSK-3-involved memory deficits.
Part II Activation GSK-3 retards calcium dependent exocytosis and the dissociation of synaptophysin I/VAMP2 complex
GSK-3 plays an important role in the development and maturation of neurons, but it is still not clear about its role in neuronal physiological functions. We found in this study that overexpressing wild type GSK-3β(wt-GSK-3β) inhibits the exocytosis in hippocampus neurons, and this inhibition mainly on the full-fusion style of vesicles. We also found that upregulation of GSK-3 phosphorylated the synprint site of P/Q calcium channel and reduced the calcium influx to trigger exocytosis. Moreover, the reduction in calcium concentration in presynapse retarded the dissociation of synaptophysin I/VAMP2 complex, which might be the molecular mechanism of exocytosis inhibition by GSK-3 activation. We conclude that upregulation GSK-3 can inhibit exocytosis through phosphorylating calcium channel in presynapse and decreasing calcium influx, indicating dysfunction of vesicle associated proteins.
Part III Activation GSK-3 inhibits anterograde axonal transport of VAMP2 mediated by kinesin light chain and its underlying mechanisms
GSK-3 is one of important kinase which is crucial in the development and mature in the neurons. Previously study had revealed that activated GSK-3 negative regulation axonal transport through phosphorylation kinesin light chain. We found in this study that overexpressing GSK-3 retards the axonal transport of VAMP2 and decreases the level of VAMP2 in distal axon. We also found that the inhibition of GSK-3 to axonal transport mainly on the inhibition to expression of KLC. We conclude that GSK-3 retards anterograde axonal transport via decreasing the expression of KLC
Part IV 17β-estradiol attenuates tau hyperphosphorylation through glycogen synthase kinase-3βinhibition independent of protein kinase B
Decline of estrogen is associated with a higher incidence of Alzheimer’s disease (AD), the most common age-associated dementia characterized pathologically with formation of numerous neurofibrillary tangles and senile plaques. The major components in the tangles and plaques are respectively the hyperphosphorylated microtubule-associated protein tau andβ-amyloid (Aβ). Previous studies have demonstrated that estrogen can efficiently attenuate Aβ-induced toxicities. However, the effect of estrogen on tau phosphorylation and the underlying mechanisms are elusive. Here, we treated the neuro2A (N2a) cells with wortmannin (Wort) and GF-109203X (GFX) to activate glycogen synthase kinase-3 (GSK-3) and thus to induce tau hyperphosphorylation. We found that 17β-estradiol (βE2) could attenuate Wort/GFX-induced tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, Ser199/202. Simultaneously, it increased the level of the Ser9-phosphorylated (inactive) GSK-3β. The effect ofβE2 on GSK-3βwas confirmed by transient overexpression of GSK-3β. To study whether the protective effect ofβE2 on GSK-3β and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. The results showed thatβE2 could attenuate Wort/GFX-induced GSK-3βactivation and tau hyperphosphorylation with Akt-independent manner. It is suggested thatβE2 may arrest AD-like tau hyperphosphorylation through directly targeting GSK-3β.
糖原合酶激酶3 (Glycogen synthase kinase-3, GSK-3)是一种在神经元的发育和成熟过程中非常重要的蛋白激酶,在引起AD样tau蛋白过度磷酸化,Aβ产生增加,导致AD样学习记忆障碍中起了重要作用,而对其引起AD样学习记忆障碍机制的研究尚缺乏。
我们在本研究中重点探讨了GSK-3在突触可塑性中的作用,重点探讨了在我们已经报道的具有AD样学习记忆障碍的动物模型上GSK-3对长时程增强(Long term potentiation, LTP)的影响并且从突触前递质释放,轴突运输,突触后形态改变,蛋白合成变化等方面探索了其内在机制。主要结果如下:
第一部分糖原合酶激酶3对突触可塑性的影响及其可能的机制
阿尔茨海默病(Alzheimer’s disease, AD)是最常见的高发于老龄人群中的痴呆疾病,激活GSK-3可以引起AD的记忆能力下降,但是其机制并不明了。我们在本研究中发现通过wortmannin和瞬时转染野生型GSK-3β(wt-GSK-3β)的质粒可以抑制大鼠海马长时程增强(long term potentiation, LTP)的诱导,而同时用锂剂或者SB216763亦或转染显性负突变GSK-3β(dn-GSK-3β)可以逆转该损伤。随着GSK-3的激活,与LTP相关的突触结构也同时受损,包括突触前活性区域减少,突触间隙变宽,突触后致密物质减少。在突触前水平,GSK-3激活时,谷氨酸释放和synapsin I(一种对调节突触释放十分重要的蛋白)在其含量和聚集上也发生了改变。我们还发现synapsin I的这种改变是不依赖于LTP的。突触后水平,我们发现PSD93和NR2A/B含量明显降低。我们认为,激活GSK-3不仅损伤突触的形态而且损伤其功能,这可能是其导致记忆损伤的机制。
第二部分糖原合酶激酶3激活阻碍钙依赖的胞吐及其机制
糖原合酶激酶3(GSK-3)在神经元的发育和成熟过程中发挥了重要的作用,而其在对神经元基本生理功能的研究尚缺乏。我们在本研究中发现,过度表达野生型GSK-3β可抑制海马神经元的胞吐现象,而且主要是通过抑制囊泡以完全融合方式的胞吐。我们还发现,激活GSK-3可降低钙离子内流以及与突触囊泡释放密切相关的Synaptophysin I/VAMP2 (囊泡相关膜蛋白2)复合体的解离障碍,激活GSK-3促进P/Q型钙通道突触结合位点的磷酸化。据此,我们推测GSK-3激活可能通过磷酸化突触前钙通道蛋白,降低钙内流,从而引发突触囊泡相关蛋白的功能紊乱,最终抑制神经元的胞吐作用。
第三部分糖原合酶激酶3激活对驱动蛋白轻链介导的VAMP2蛋白顺向轴突转运的抑制作用及其机制
糖原合酶激酶3(GSK-3)是一种在在神经元的发育和成熟过程中发挥了重要的作用的蛋白激酶,前期的报道显示激活GSK-3可以通过磷酸化驱动蛋白轻链蛋白(KLC)来负性调节轴突运输。我们的研究中发现,过度表达GSK-3可以使VAMP2蛋白的轴突转运受到阻抑,从而使到达轴突远端的VAMP2蛋白含量降低。我们还发现,GSK-3这种对轴突运输的阻抑作用可能是通过其对KLC的蛋白表达的抑制引起的。因此,我们推测GSK-3可能通过降低KLC的量进而阻滞其介导的顺向轴突转运。
第四部分雌激素对糖原合酶激酶3激活引起的tau蛋白过度磷酸化的保护作用
雌激素水平的降低与阿尔茨海默病(AD)的高发性密切相关。阿尔茨海默病(AD)是最常见的与年龄相关的痴呆病之一,其病理学特征为神经原纤维缠结(NFTs)和老年斑(SP)。过度磷酸化的微管相关蛋白和β样淀粉蛋白(Aβ)分别构成了神经纤维缠结和老年斑的主要成分。先前有研究表明雌激素能有效缓解Aβ引起的细胞毒性。然而,雌激素是否同样影响tau蛋白磷酸化?其潜在的机制又如何呢?在这篇文章中,我们给予wortmannin (Wort)和GF-109203X (GFX)处理neuro2A (N2a)细胞,以激活糖原合成激酶-3(GSK-3),诱导出tau蛋白过度磷酸化模型。在这个实验中,我们发现17β-雌二醇(βE2)能够缓解Wort/GFX-诱导的与众多AD-相关位点上的tau蛋白的过度磷酸化,如Ser396/404,Thr231,Thr205,Ser199/202。同时,βE2还能使非活性形式的GSK-3β(Ser9位磷酸化)增加。βE2对GSK-3β的作用通过瞬时过度表达GSK-3β得到确证。为了证明βE2对GSK-3β和tau蛋白磷酸化的保护作用是否通过GSK-3的上游因子之一----蛋白激酶B(Akt)?我们在N2a细胞上瞬时转染了显性负突变Akt质粒(dn-Akt)。结果显示,βE2对Wort/GFX-诱导的GSK-3β的激活和tau蛋白的过度磷酸化的缓解作用是不依赖于Akt的。这就提示βE2通过直接作用于GSK-3β来减少AD样tau蛋白的过度磷酸化。
Alzheimer’s disease (AD) is the most popular dementia in aged people. The main pathological hallmarks in AD are the formation of intracellular neurofibrillary tangles consisted of hyperphosphorylated tau, extracellular senile plaques consisted ofβ-amyloid (Aβ) peptide, neuronal loss caused by dystrophic neuritis. The main character of AD in clinical is progressive memory loss. Previously studies had revealed that the dysfunction of synaptic plasticity is the primary reason for learning/memory deficits in AD.
Glycogen synthase kinase-3 (GSK-3) is a crucial protein kinase which is necessary for the development and maturity of neuron. It is also known that GSK-3 plays an important role in the pathogenesis of AD, such as induces tau hyperphosphorylation, increases the production of Aβand leads to AD-like learning/memory deficits. However, the mechanisms of GSK-3 induce AD-like learning/memory deficits is still unknown.
In the present study, we aimed to investigate the role of GSK-3 in synaptic plasticity, especially on the effect of GSK-3 activation to LTP in our previously reported animal model with AD-like learning/memory deficits. We also explore the underlying mechanisms through the changing of presynaptic neurotransmitter releasing, axonal transport, morphological changes in post-synpase and protein synthesis. The main results are as following:
Part I Activation of glycogen synthase kinase-3 inhibits long term potentiation with synapse-associated impairments
Activation of glycogen synthase kinase-3 (GSK-3) can cause memory deficits as seen in Alzheimer’s disease (AD), the most common age-associated dementia, but the mechanism is not understood. Here, we found that activation of GSK-3 by wortmannin or transient overexpression of wild type GSK-3β(wt-GSK-3β) could suppress the induction of long term potentiation (LTP) in rat hippocampus, while simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant negative GSK-3βmutant (dn-GSK-3β) preserved the LTP. With activation of GSK-3, prominent LTP-associated synapse impairments including less presynaptic active zone, thinner postsynaptic density (PSD) and broader synaptic cleft were observed in the hippocampal slices after high frequency stimulation (HFS). In presynaptic level, the release of glutamate and the expression/clustering of synapsin I, a synaptic vesicle protein playing an important role in neurotransmitter release, decreased markedly upon upregulation of GSK-3. In vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of HFS. In postsynaptic level, the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was activated. These synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of dnGSK-3. We conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally, which may underlie the GSK-3-involved memory deficits.
Part II Activation GSK-3 retards calcium dependent exocytosis and the dissociation of synaptophysin I/VAMP2 complex
GSK-3 plays an important role in the development and maturation of neurons, but it is still not clear about its role in neuronal physiological functions. We found in this study that overexpressing wild type GSK-3β(wt-GSK-3β) inhibits the exocytosis in hippocampus neurons, and this inhibition mainly on the full-fusion style of vesicles. We also found that upregulation of GSK-3 phosphorylated the synprint site of P/Q calcium channel and reduced the calcium influx to trigger exocytosis. Moreover, the reduction in calcium concentration in presynapse retarded the dissociation of synaptophysin I/VAMP2 complex, which might be the molecular mechanism of exocytosis inhibition by GSK-3 activation. We conclude that upregulation GSK-3 can inhibit exocytosis through phosphorylating calcium channel in presynapse and decreasing calcium influx, indicating dysfunction of vesicle associated proteins.
Part III Activation GSK-3 inhibits anterograde axonal transport of VAMP2 mediated by kinesin light chain and its underlying mechanisms
GSK-3 is one of important kinase which is crucial in the development and mature in the neurons. Previously study had revealed that activated GSK-3 negative regulation axonal transport through phosphorylation kinesin light chain. We found in this study that overexpressing GSK-3 retards the axonal transport of VAMP2 and decreases the level of VAMP2 in distal axon. We also found that the inhibition of GSK-3 to axonal transport mainly on the inhibition to expression of KLC. We conclude that GSK-3 retards anterograde axonal transport via decreasing the expression of KLC
Part IV 17β-estradiol attenuates tau hyperphosphorylation through glycogen synthase kinase-3βinhibition independent of protein kinase B
Decline of estrogen is associated with a higher incidence of Alzheimer’s disease (AD), the most common age-associated dementia characterized pathologically with formation of numerous neurofibrillary tangles and senile plaques. The major components in the tangles and plaques are respectively the hyperphosphorylated microtubule-associated protein tau andβ-amyloid (Aβ). Previous studies have demonstrated that estrogen can efficiently attenuate Aβ-induced toxicities. However, the effect of estrogen on tau phosphorylation and the underlying mechanisms are elusive. Here, we treated the neuro2A (N2a) cells with wortmannin (Wort) and GF-109203X (GFX) to activate glycogen synthase kinase-3 (GSK-3) and thus to induce tau hyperphosphorylation. We found that 17β-estradiol (βE2) could attenuate Wort/GFX-induced tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, Ser199/202. Simultaneously, it increased the level of the Ser9-phosphorylated (inactive) GSK-3β. The effect ofβE2 on GSK-3βwas confirmed by transient overexpression of GSK-3β. To study whether the protective effect ofβE2 on GSK-3β and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. The results showed thatβE2 could attenuate Wort/GFX-induced GSK-3βactivation and tau hyperphosphorylation with Akt-independent manner. It is suggested thatβE2 may arrest AD-like tau hyperphosphorylation through directly targeting GSK-3β.
引文
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