ATP synthase α抑制Aβ神经毒性损伤的机制研究
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摘要
阿尔茨海默病(Alzheimer's disease, AD)是一种脑神经元进行性变性的痴呆性疾病。AD的神经病理标志是脑内分布有大量的β-淀粉样蛋白(β-amyloid,Aβ)沉积形成老年斑(senile plaque, SP),神经元内过度磷酸化tau蛋白聚集形成神经原纤维缠结(neurofibrillary tangle),神经元的营养障碍(Neuronal dystrophy)以及神经元大量缺失,突触的损害和丢失。但其具体的机制还不是很清楚,目前对于AD的发生机制提出了多种假设,主要包括p淀粉样蛋白级联假说、tau蛋白过度磷酸化假说、胆碱能假说、基因假说、金属离子假说和突触功能障碍假说等。十几年前Selkoe和Hardy及Higgins等提出Ap假说,该假说解释了AD的发生原因,并且为治疗该疾病提供了依据。而Aβ神经毒性是各种因素引起AD的共同通路,是AD形成和发展的关键因素。因此,近年来AD的治疗研究,大多围绕Ap的形成、聚集以及清除或Ap的神经毒性机制进行。
Ap的毒性作用依赖于它的聚集,因此,抑制Ap的聚集成为治疗AD的有效的手段,目前用于抑制Aβ聚集的物质有多种,大量的报道证实热休克蛋白可以抑制Aβ聚集。ATP合酶(ATP synthase)α亚单位被认为是一种热休克蛋白,并与Aβ相互作用,因此,也成为研究的热点。
ATP合酶又称为F0F1-ATPase,是一个酶复合物,负责ADP的氧化磷酸化驱动的ATP合成,该酶是通常定位于线粒体内膜,除了在线粒体外还在细胞的其他部位分布,如细胞浆膜上。细胞浆膜上ATP合酶可作为受体介导血管形成、肿瘤存活的调节和细胞内pH调节。值得注意的是,近期的证据显示FOF1-ATP合酶α亚单位可能在神经退行性疾病中发挥重要的作用,例如：在AD病人前脑皮质F0F1-ATP合酶表达增加；ATP合酶在PD病人标本中含量增加两倍；ATP合酶α亚单位能与Aβ和APP结合,也与神经纤维退行性相关。
ATP合酶α亚单位可归为热休克蛋白(Heat Shock Protein, HSP)家族,热休克蛋白的主要功能为抑制误折叠的多肽和抑制蛋白质聚集。已发现HSP 70、90,以及小热休克蛋白如HSP22、27均可抑制Ap的聚集和Ap引起的细胞毒性作用。ATP合酶的α亚单位与HSP60的DNA序列具有一定的同源性,尤其在具有分子伴侣功能的两个保守的元件中具有极高的同源性。我们实验室研究发现ATP合酶α亚单位可以降低突变型亨廷顿蛋白(Mutant huntingtin, mhtt)的聚集,减小mhtt对神经细胞的毒性作用。鉴于FoF1-ATP合酶a亚单位有HSP样的功能,及其在AD脑内的异常表达。我们推测ATP合酶a亚单位可能参与抑制Aβ诱导损伤的机制。因此,本课题研究ATP合酶α亚单位是否抑制Aβ诱导的神经毒性损伤,并探讨其机制,
主要研究内容如下：
1.构建的构建、鉴定和定位
构建含有成熟型的ATP合酶a亚单位cDNA的表达载体(pDsRed-N1-ATP syn),PCR和酶切鉴定及DNA测序结果显示载体构建成功,插入序列为ATP syn(M)的DNA片段。Western Blot结果显示有重组蛋白(ATP syn)的阳性条带出现。免疫荧光组化结果显示细胞内有红色荧光蛋白表达。免疫荧光标记结果显示,ATP合酶α亚单位与APP或TOM或者TIM在线粒体内共定位。
2.ATP合酶α亚单位过表达对Ap介导的细胞损伤和线粒体膜电位降低的调节
纤维状Ap处理情况下可快速上调ATP合酶α亚单位表达。在SY-SH5Y细胞转染pDsRed-N1-ATP syn,纤维状Aβ处理情况下,MTT检测细胞的活力,结果显示与转染空载体DsRed的对照相比,ATP合酶α亚单位过表达情况下,OD值显著增加,提示,ATP合酶α亚单位过表达可抑制Aβ诱导的细胞损伤。同时,WST检测结果显示,表达DsRed-ATP syn融合蛋白的细胞株具有较高的活力。进一步提示,ATP合酶α亚单位过表达可抑制Aβ介导的神经毒性。罗丹明123荧光染色检测线粒体膜电位,结果显示,过表达ATP syn的细胞株的线粒体膜电位明显高于表达空质粒的细胞,提示ATP合酶α亚单位可抑制Aβ引起的细胞毒性介导的线粒体损害。
3.ATP合酶α亚单位过表达下调Ap介导的Bax/ Bcl-2比值和活化型caspase-3的增加,可上调Ap诱导的HSP70和ATP合酶p亚单位的表达。
稳定表达ATP syn的细胞株给予Ap处理24h,Western blot的结果显示,与转染空载体pDsRed-N 1的细胞组相比,转染了pDsRed-N 1-ATP syn DNA的细胞在Aβ处理后,其Bax/Bcl-2比值和活化型caspase-3均明显小于对照组,提示ATP合酶α亚单位可抑制Ap诱导的凋亡相关蛋白表达及caspase-3激活。另外,ATP合酶α亚单位过表达可调节Ap诱导的HSP70和ATP合酶p亚单位的表达。
4.ATP合酶α亚单位原核表达载体的构建
对载体中的基因进行PCR鉴定和酶切鉴定结果与理论预测值一致,且DNA测序分析结果进一步证实该表达载体pGEX-4T2-ATP-syn构建的成功。IPTG诱导后,SDS-PAGE电泳结果显示,在79kD处新增一条富聚的条带,与预测的GST-ATP syn融合蛋白大小一致。在优化诱导表达和分离条件的基础上,大量表达并用GST亲和纯化,用凝血酶酶切切去GST,在经过GST亲和纯化获得ATP synα。
5.ATP可协同ATP合酶α亚单位抑制Aβ的聚集,但不能解聚纤维状Aβ,ATP也不能促进ATP合酶α亚单位解聚纤维状Aβ这种情况。
原核表达的ATP合酶α亚单位与Aβ共孵育不同时间,ThT法检测Ap的荧光强度,结果显示,Aβ和ATP合酶α亚单位组荧光强度明显降低,提示,ATP合酶α亚单位抑制Aβ的聚集,且在ATP存在的情况下,ATP合酶a亚单位抑制Aβ聚集的作用更明显,提示ATP可协同ATP合酶α亚单位抑制Aβ的聚集。此外,浊度法结果同样提示,ATP合酶α亚单位抑制Ap的聚集。解聚实验结果提示,ATP合酶α亚单位不能解聚纤维状的Aβ,ATP不能促进ATP合酶α亚单位的这种解聚作用。
6.在AD转基因动物脑内的老年斑内有ATP合酶α亚单位的分布增加,但β亚单位没有增加。
总之,ATP合酶α亚单位可以抑制Aβ介导的神经毒性损伤,并且抑制Aβ的聚集,但是对纤维状Ap无解聚作用,同时,ATP能增加ATP合酶α亚单位对Aβ聚集抑制。可能对AD的治疗具有重要的指导意义。
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by deposition of extracellular senile plaques formed by accumulatedβ-amyloid proteins (AP), accumulation of intracellular neurofibrillary tangles formed by abnormal phosphorylated tau, neuronal dystrophy and neuronal cell loss. P-amyloid precursor protein (APP), a transmembrane protein, is important for the pathophysiology of AD. Aβpeptide is generated by proteolysis of APP. Most of previous attentions have been focused on the neurotoxicity of Aβ.
The F0F1-ATP synthase is the enzyme complex responsible for ATP synthesis driven by oxidative phosphorylation. The complex is a molecular motor that normally operates as an ATP synthase in the mitochondrial inner membrane in which ADP phosphorylation is driven by the movement of protons along the electrochemical potential gradient established by respiration. During conditions of reduced membrane, the ability of the F0F1-ATP synthase to reverse by hydrolyzing ATP and generating an electrochemical proton gradient across a membrane to support locomotion or nutrient uptake and act as an ATPase potential has been appreciated for many years.
Many reports from several laboratories in recent years have concerned the location and function of the ATP synthase complex or its component subunits on the external surface of the plasma membrane of various mammalian cell types, including vascular endothelial cells, hepatocytes, adipocytes and tumor cells. F0F1 components, especialy a subunit, have been identified as cell-surface receptors for multiple ligands in studies of angiogenesis, tumor proliferation/toxicity, lipid/lipoprotein metabolism, immune recognition of tumors, hypertension, the synthesis of ATP, the regulation of intercellular pH, and the cytolytic pathway of tumor cells.
Currently, mounting evidences indicate ATP synthase a may play a role in neurodegenerative diseases, including AD and PD. For example, increased ATP synthase levels were found in the frontal cortex in PD. ATP synthase has a twofold higher abundance in PD specimens. ATP synthase a can bind the extracellular domain of APP and Aβ. A study showed that Aβ25-35 can induce the expression of ATP synthaseα-chain in primary rat cortical neurons. An interesting research showed that ATP synthase a-chain associated with neurofibrillary degeneration accumulate in the cytosol of Alzheimer degenerating neurons in AD. However, little is understood about the role of ATP synthase a in cell death and neurodegeneration.
Recent reports have also implicated that the nuclear coded F0F1-ATP synthase a physically interacts with HSP60, which is known to stabilize numerous mitochondrial proteins and HSP90. We studied the role of ATP synthase a in mhtt aggregate formation in SH-SY5Y cells. The studies reporte demonstrated that ATP synthas areduced aggregate formation and neurotoxicity in cultured neuronal cells expressing htt protein with an expanded polyglutamine tract. We previously studied the role of ATP synthase a in mhtt aggregate formation in SH-SY5Y cells. Results demonstrated that ATP synthase a reduced aggregate formation and neurotoxicity in cultured neuronal cells expressing htt protein with an expanded polyglutamine tract.
These and other results have stimulated the search for pharmacological compounds capable of up-regulatinga subunit of ATP synthase expression, thus such compounds would theoretically have potential as treatments for these and other neurologic disorders. In this light very promising, in this study, we investigated whether ATP synthase a protecting the SH-SY5Y cells from Aβ25-35-induced oxidative cell death, and explored the underlying protective mechanisms. The results were summarized as follows:
1. In this study, we cloned ATP syn a cDNA, and constructed pDsRed-N 1-ATP syn-αplasmid. After treansfected into SH-SY5Y cells, westen blot detected DsRed-ATP syna bands, and showed DsRed-ATP syn a in mitochrondia marker TOM or TIM labeled subcellular structures.
2. First, we showed that Aβcould induced an increase of ATP syn-a in SH-SY5Y cell. The overexpression of a subunit of ATP synthase protected beta-amyloid-induced cytotoxicity and regulated the expression of Bcl-2 family proteins and to decrease the activation of caspase-3. The a subunit of ATP synthase ameliorated Aβ25-35-induced cell injury. The overexpression of a subunit of ATP synthase protected SH-SY5Y cells against Aβ25-35-induced cell apoptosis and death showed by MTT assay. WST assay also showed that the overexpression of a subunit of ATP synthase inhibited Aβ25-35-induced cell injury in SH-SY5Y cells transfected with pDsRed-Nl-ATP syn compared that transfected with pDsRed-N 1 DNA.
3. The overexpression of a subunit of ATP synthase inhibited Aβ25-35-induced dissipation of the mitochondrial membrane potential (MMP) monitored using the Rh123 in SH-SY5Y cells transfected with pDsRed-Nl-ATP syn compared to transfected with pDsRed-N1 DNA. After Aβtreatment, the overexpression ofαsubunit of ATP synthase increased the Bcl-2/Bax ratio in SH-SY5Y cells transfected with pDsRed-N1-ATP compared to the cells pDsRed-N1 DNA detected by Western blot. The overexpression ofαsubunit of ATP synthase also downregulated the caspase-3 activation in SH-SY5Y cells transfected with pDsRed-N1-ATP syn compared to that transfected with pDsRed-N1 DNA.
4. In this study, we constructed pGEX-4T2-ATP-syn-αplasmid, and expressed and purified ATP-syn-α. With turbid assay and Thioflavin T measurement, experiments showed thatαsubunit of ATP synthase counteract the the aggregation of amyloid Aβin vitro and the anti-aggregation activity ofαsubunit of ATP synthase was enhanced by ATP. These effects are not only for Aβ25-35 but also for Aβ1-40 in vitro
5. With turbid assay and Thioflavin T measurement, we showed thatαsubunit of ATP synthase did not disassemble existing fibrils Aβ. ATP synthaseαincubated with Aβ25-35 and Aβ1-40 did not disassemble existing fibrils Aβ25-35 and Aβ1-40. Addition of ATP did not induce the function of ATP synthaseαfor Aβdisassembly.
5. By immunostaining and Thioflavin S staining, we observed that in amyloid plaques of APPswe/PS1ΔE9 AD mice, there are many amyloid plaques with high level ofαsubunit of ATP synthase, but notβsubunit of ATP synthase.
In summary, we described that amyloid could induced the increase of ATP synthaseαexpression, the increased ATP synthaseαcould inhibited amyloid toxicity. Moreover, ATP synthaseαcould inhibited amyloid aggregation but did not disassemble aggregated amyloid. In addition, ATP synthaseαin amyloid plaques of AD transgenic mice, imply that ATP synthaseαmight try to inhibit amyloid aggregation.
Ap的毒性作用依赖于它的聚集,因此,抑制Ap的聚集成为治疗AD的有效的手段,目前用于抑制Aβ聚集的物质有多种,大量的报道证实热休克蛋白可以抑制Aβ聚集。ATP合酶(ATP synthase)α亚单位被认为是一种热休克蛋白,并与Aβ相互作用,因此,也成为研究的热点。
ATP合酶又称为F0F1-ATPase,是一个酶复合物,负责ADP的氧化磷酸化驱动的ATP合成,该酶是通常定位于线粒体内膜,除了在线粒体外还在细胞的其他部位分布,如细胞浆膜上。细胞浆膜上ATP合酶可作为受体介导血管形成、肿瘤存活的调节和细胞内pH调节。值得注意的是,近期的证据显示FOF1-ATP合酶α亚单位可能在神经退行性疾病中发挥重要的作用,例如：在AD病人前脑皮质F0F1-ATP合酶表达增加；ATP合酶在PD病人标本中含量增加两倍；ATP合酶α亚单位能与Aβ和APP结合,也与神经纤维退行性相关。
ATP合酶α亚单位可归为热休克蛋白(Heat Shock Protein, HSP)家族,热休克蛋白的主要功能为抑制误折叠的多肽和抑制蛋白质聚集。已发现HSP 70、90,以及小热休克蛋白如HSP22、27均可抑制Ap的聚集和Ap引起的细胞毒性作用。ATP合酶的α亚单位与HSP60的DNA序列具有一定的同源性,尤其在具有分子伴侣功能的两个保守的元件中具有极高的同源性。我们实验室研究发现ATP合酶α亚单位可以降低突变型亨廷顿蛋白(Mutant huntingtin, mhtt)的聚集,减小mhtt对神经细胞的毒性作用。鉴于FoF1-ATP合酶a亚单位有HSP样的功能,及其在AD脑内的异常表达。我们推测ATP合酶a亚单位可能参与抑制Aβ诱导损伤的机制。因此,本课题研究ATP合酶α亚单位是否抑制Aβ诱导的神经毒性损伤,并探讨其机制,
主要研究内容如下：
1.构建的构建、鉴定和定位
构建含有成熟型的ATP合酶a亚单位cDNA的表达载体(pDsRed-N1-ATP syn),PCR和酶切鉴定及DNA测序结果显示载体构建成功,插入序列为ATP syn(M)的DNA片段。Western Blot结果显示有重组蛋白(ATP syn)的阳性条带出现。免疫荧光组化结果显示细胞内有红色荧光蛋白表达。免疫荧光标记结果显示,ATP合酶α亚单位与APP或TOM或者TIM在线粒体内共定位。
2.ATP合酶α亚单位过表达对Ap介导的细胞损伤和线粒体膜电位降低的调节
纤维状Ap处理情况下可快速上调ATP合酶α亚单位表达。在SY-SH5Y细胞转染pDsRed-N1-ATP syn,纤维状Aβ处理情况下,MTT检测细胞的活力,结果显示与转染空载体DsRed的对照相比,ATP合酶α亚单位过表达情况下,OD值显著增加,提示,ATP合酶α亚单位过表达可抑制Aβ诱导的细胞损伤。同时,WST检测结果显示,表达DsRed-ATP syn融合蛋白的细胞株具有较高的活力。进一步提示,ATP合酶α亚单位过表达可抑制Aβ介导的神经毒性。罗丹明123荧光染色检测线粒体膜电位,结果显示,过表达ATP syn的细胞株的线粒体膜电位明显高于表达空质粒的细胞,提示ATP合酶α亚单位可抑制Aβ引起的细胞毒性介导的线粒体损害。
3.ATP合酶α亚单位过表达下调Ap介导的Bax/ Bcl-2比值和活化型caspase-3的增加,可上调Ap诱导的HSP70和ATP合酶p亚单位的表达。
稳定表达ATP syn的细胞株给予Ap处理24h,Western blot的结果显示,与转染空载体pDsRed-N 1的细胞组相比,转染了pDsRed-N 1-ATP syn DNA的细胞在Aβ处理后,其Bax/Bcl-2比值和活化型caspase-3均明显小于对照组,提示ATP合酶α亚单位可抑制Ap诱导的凋亡相关蛋白表达及caspase-3激活。另外,ATP合酶α亚单位过表达可调节Ap诱导的HSP70和ATP合酶p亚单位的表达。
4.ATP合酶α亚单位原核表达载体的构建
对载体中的基因进行PCR鉴定和酶切鉴定结果与理论预测值一致,且DNA测序分析结果进一步证实该表达载体pGEX-4T2-ATP-syn构建的成功。IPTG诱导后,SDS-PAGE电泳结果显示,在79kD处新增一条富聚的条带,与预测的GST-ATP syn融合蛋白大小一致。在优化诱导表达和分离条件的基础上,大量表达并用GST亲和纯化,用凝血酶酶切切去GST,在经过GST亲和纯化获得ATP synα。
5.ATP可协同ATP合酶α亚单位抑制Aβ的聚集,但不能解聚纤维状Aβ,ATP也不能促进ATP合酶α亚单位解聚纤维状Aβ这种情况。
原核表达的ATP合酶α亚单位与Aβ共孵育不同时间,ThT法检测Ap的荧光强度,结果显示,Aβ和ATP合酶α亚单位组荧光强度明显降低,提示,ATP合酶α亚单位抑制Aβ的聚集,且在ATP存在的情况下,ATP合酶a亚单位抑制Aβ聚集的作用更明显,提示ATP可协同ATP合酶α亚单位抑制Aβ的聚集。此外,浊度法结果同样提示,ATP合酶α亚单位抑制Ap的聚集。解聚实验结果提示,ATP合酶α亚单位不能解聚纤维状的Aβ,ATP不能促进ATP合酶α亚单位的这种解聚作用。
6.在AD转基因动物脑内的老年斑内有ATP合酶α亚单位的分布增加,但β亚单位没有增加。
总之,ATP合酶α亚单位可以抑制Aβ介导的神经毒性损伤,并且抑制Aβ的聚集,但是对纤维状Ap无解聚作用,同时,ATP能增加ATP合酶α亚单位对Aβ聚集抑制。可能对AD的治疗具有重要的指导意义。
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by deposition of extracellular senile plaques formed by accumulatedβ-amyloid proteins (AP), accumulation of intracellular neurofibrillary tangles formed by abnormal phosphorylated tau, neuronal dystrophy and neuronal cell loss. P-amyloid precursor protein (APP), a transmembrane protein, is important for the pathophysiology of AD. Aβpeptide is generated by proteolysis of APP. Most of previous attentions have been focused on the neurotoxicity of Aβ.
The F0F1-ATP synthase is the enzyme complex responsible for ATP synthesis driven by oxidative phosphorylation. The complex is a molecular motor that normally operates as an ATP synthase in the mitochondrial inner membrane in which ADP phosphorylation is driven by the movement of protons along the electrochemical potential gradient established by respiration. During conditions of reduced membrane, the ability of the F0F1-ATP synthase to reverse by hydrolyzing ATP and generating an electrochemical proton gradient across a membrane to support locomotion or nutrient uptake and act as an ATPase potential has been appreciated for many years.
Many reports from several laboratories in recent years have concerned the location and function of the ATP synthase complex or its component subunits on the external surface of the plasma membrane of various mammalian cell types, including vascular endothelial cells, hepatocytes, adipocytes and tumor cells. F0F1 components, especialy a subunit, have been identified as cell-surface receptors for multiple ligands in studies of angiogenesis, tumor proliferation/toxicity, lipid/lipoprotein metabolism, immune recognition of tumors, hypertension, the synthesis of ATP, the regulation of intercellular pH, and the cytolytic pathway of tumor cells.
Currently, mounting evidences indicate ATP synthase a may play a role in neurodegenerative diseases, including AD and PD. For example, increased ATP synthase levels were found in the frontal cortex in PD. ATP synthase has a twofold higher abundance in PD specimens. ATP synthase a can bind the extracellular domain of APP and Aβ. A study showed that Aβ25-35 can induce the expression of ATP synthaseα-chain in primary rat cortical neurons. An interesting research showed that ATP synthase a-chain associated with neurofibrillary degeneration accumulate in the cytosol of Alzheimer degenerating neurons in AD. However, little is understood about the role of ATP synthase a in cell death and neurodegeneration.
Recent reports have also implicated that the nuclear coded F0F1-ATP synthase a physically interacts with HSP60, which is known to stabilize numerous mitochondrial proteins and HSP90. We studied the role of ATP synthase a in mhtt aggregate formation in SH-SY5Y cells. The studies reporte demonstrated that ATP synthas areduced aggregate formation and neurotoxicity in cultured neuronal cells expressing htt protein with an expanded polyglutamine tract. We previously studied the role of ATP synthase a in mhtt aggregate formation in SH-SY5Y cells. Results demonstrated that ATP synthase a reduced aggregate formation and neurotoxicity in cultured neuronal cells expressing htt protein with an expanded polyglutamine tract.
These and other results have stimulated the search for pharmacological compounds capable of up-regulatinga subunit of ATP synthase expression, thus such compounds would theoretically have potential as treatments for these and other neurologic disorders. In this light very promising, in this study, we investigated whether ATP synthase a protecting the SH-SY5Y cells from Aβ25-35-induced oxidative cell death, and explored the underlying protective mechanisms. The results were summarized as follows:
1. In this study, we cloned ATP syn a cDNA, and constructed pDsRed-N 1-ATP syn-αplasmid. After treansfected into SH-SY5Y cells, westen blot detected DsRed-ATP syna bands, and showed DsRed-ATP syn a in mitochrondia marker TOM or TIM labeled subcellular structures.
2. First, we showed that Aβcould induced an increase of ATP syn-a in SH-SY5Y cell. The overexpression of a subunit of ATP synthase protected beta-amyloid-induced cytotoxicity and regulated the expression of Bcl-2 family proteins and to decrease the activation of caspase-3. The a subunit of ATP synthase ameliorated Aβ25-35-induced cell injury. The overexpression of a subunit of ATP synthase protected SH-SY5Y cells against Aβ25-35-induced cell apoptosis and death showed by MTT assay. WST assay also showed that the overexpression of a subunit of ATP synthase inhibited Aβ25-35-induced cell injury in SH-SY5Y cells transfected with pDsRed-Nl-ATP syn compared that transfected with pDsRed-N 1 DNA.
3. The overexpression of a subunit of ATP synthase inhibited Aβ25-35-induced dissipation of the mitochondrial membrane potential (MMP) monitored using the Rh123 in SH-SY5Y cells transfected with pDsRed-Nl-ATP syn compared to transfected with pDsRed-N1 DNA. After Aβtreatment, the overexpression ofαsubunit of ATP synthase increased the Bcl-2/Bax ratio in SH-SY5Y cells transfected with pDsRed-N1-ATP compared to the cells pDsRed-N1 DNA detected by Western blot. The overexpression ofαsubunit of ATP synthase also downregulated the caspase-3 activation in SH-SY5Y cells transfected with pDsRed-N1-ATP syn compared to that transfected with pDsRed-N1 DNA.
4. In this study, we constructed pGEX-4T2-ATP-syn-αplasmid, and expressed and purified ATP-syn-α. With turbid assay and Thioflavin T measurement, experiments showed thatαsubunit of ATP synthase counteract the the aggregation of amyloid Aβin vitro and the anti-aggregation activity ofαsubunit of ATP synthase was enhanced by ATP. These effects are not only for Aβ25-35 but also for Aβ1-40 in vitro
5. With turbid assay and Thioflavin T measurement, we showed thatαsubunit of ATP synthase did not disassemble existing fibrils Aβ. ATP synthaseαincubated with Aβ25-35 and Aβ1-40 did not disassemble existing fibrils Aβ25-35 and Aβ1-40. Addition of ATP did not induce the function of ATP synthaseαfor Aβdisassembly.
5. By immunostaining and Thioflavin S staining, we observed that in amyloid plaques of APPswe/PS1ΔE9 AD mice, there are many amyloid plaques with high level ofαsubunit of ATP synthase, but notβsubunit of ATP synthase.
In summary, we described that amyloid could induced the increase of ATP synthaseαexpression, the increased ATP synthaseαcould inhibited amyloid toxicity. Moreover, ATP synthaseαcould inhibited amyloid aggregation but did not disassemble aggregated amyloid. In addition, ATP synthaseαin amyloid plaques of AD transgenic mice, imply that ATP synthaseαmight try to inhibit amyloid aggregation.
引文
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