糖皮质激素对星形胶质细胞β淀粉样蛋白代谢的影响及其在Alzheimer's病发病中的作用与机制研究
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摘要
阿尔茨海默氏病(Alzheimer’s Disease, AD)是以进行性学习记忆和认知功能障碍为特征,最终导致患者生活能力丧失的一种老年性神经退行性疾病。该病严重损害老年人的身心健康,已成为致人类死亡的第四大疾病,同时也是影响家庭和社会发展的重要制约因素之一。AD依据有无遗传史可分为家族性和散发性,其典型的神经病理学特征是淀粉样蛋白(amyloidβ-peptide,Aβ)斑和tau蛋白沉积形成的神经原纤维缠结。尽管已发现有3种基因的突变可以引起稀有的家族性遗传AD,但大多数AD病人(90–95%)属于非遗传性的散发性迟发性AD (≥65岁) (late-onset AD,LOAD),病因至今仍不清楚。流行病学调查结果证明,应激是AD的危险因素,发生心理不良应激的老年人比同年龄人更易于发生AD,丰富的环境可以降低Aβ水平和蛋白斑形成。目前认为,散发性AD的发生是多种不同的遗传和环境因素共同作用的结果。因此,深入研究AD的发病原因与机理,特别是研究遗传以外的环境因素如何影响散发性AD的发病,将在防治AD、维护老年人健康方面起到积极的作用,具有极其重要的理论和实际意义。
在众多的环境因素中,应激等精神心理因素如抑郁、焦虑等在神经退行性疾病发病中的作用日益受到重视。应激反应的基础是体内一系列神经-内分泌-免疫网络系统反应,应激相关的神经内分泌激素很可能是AD发生发展过程中重要的因素。糖皮质激素(Glucocorticoids,GC)属于类固醇激素,容易穿过血脑屏障结合糖皮质激素受体(Glucocorticoid Receptors, GR)。现已证实, GC对于中枢神经系统(Central Nervous System,CNS)的许多功能,包括学习和记忆都非常重要,但在应激中产生的过量GC会损害认知功能。GC对应激刺激的反应受下丘脑-垂体-肾上腺(Hypothalamic–Pituitary–Adrenal,HPA)轴的调控,由肾上腺皮质释放GC(灵长类是皮质醇,啮齿类是皮质酮)。流行病学调查表明AD病人中HPA轴功能失调,表现为循环水平的皮质醇水平显著升高。因此,GC作为应激反应中重要的神经内分泌激素很可能参与AD的发生发展。
在AD发病机理的研究方面,目前大多数学者都认为,大脑Aβ的代谢异常——包括过度产生或降解减少,引起Aβ聚合沉积形成β淀粉样蛋白斑在AD的发生发展中起关键作用。Aβ是淀粉样前体蛋白(amyloid precursor protein,APP)被β分泌酶(APP的β位点裂解酶,β-site APP cleaving enzyme,BACE)和γ分泌酶相继裂解的产物。以往对AD发病中Aβ代谢异常的研究主要集中于大脑的神经元,实验发现,GC可通过影响神经元Aβ代谢,从而对AD的发生发展起一定的促进作用。近年来,星形胶质细胞在AD发病中的重要作用越来越受到关注。研究表明,星形胶质细胞具有分泌和降解清除Aβ的双重功能。一方面,在对转基因AD小鼠和AD病人的研究中发现,星形胶质细胞来源的Aβ参与蛋白斑形成和成熟,只是在时相上晚于神经元。另一方面,对老年AD病人大脑的尸检分析,常可观察到Aβ斑块周围存在大量的星形胶质细胞,进一步的实验证实增生和活化的星形胶质细胞可以吞噬和降解Aβ。有资料显示:GC能调控星形胶质细胞的增殖、分化过程以及细胞因子的分泌,是神经退行性疾病中影响星形胶质细胞代谢的关键激素。但迄今为止,有关GC是否影响星形胶质细胞Aβ的代谢过程,参与AD的发病尚未见报道。
在本研究中,我们使用应激浓度的GC,通过体内外实验研究GC对星形胶质细胞Aβ代谢的效应和机制,以及对AD病理的影响。期望从星形胶质细胞调控Aβ代谢的新角度认识GC在AD发生发展中的作用,为深入理解散发性AD的发病机制提供新的理论依据,并为寻找有效防治靶点提供线索。
本文的主要研究内容及结果包括:
1.证实了GC能够促进星形胶质细胞生成Aβ。
建立了体外GC刺激星形胶质细胞分泌Aβ的模型:利用AdEASY腺病毒系统在293细胞成功表达了含APPSW突变型和APP野生型的腺病毒,用腺病毒感染原代星形胶质细胞后,加入地塞米松或者皮质酮检测对Aβ分泌的影响。结果显示,在未受刺激的条件下,星形胶质细胞基本不分泌Aβ,糖皮质激素可以促进星形胶质细胞分泌Aβ,并且和刺激剂量及时间呈正相关关系。
2.明确了GC促进星形胶质细胞生成Aβ的效应通路。
首先,检测了GC发挥作用是通过GC的基因组效应还是非基因组效应实现的。结果发现,用不可穿过胞膜的BSA偶联的皮质酮刺激星形胶质细胞无促进Aβ分泌的作用,说明GC的效应是通过基因组效应实现的。其次,检测了GC发挥基因组效应的受体通路。结果显示,GR的拮抗剂米非司酮(mifepristone,RU 38486)可以完全阻断GC促进星形胶质细胞分泌Aβ的作用,相反盐皮质激素受体(mineralocorticoid receptor,MR)的拮抗剂安体舒通(spironolactone,RU 28318)对GC该效应没有明显抑制,进一步说明GC促进星形胶质细胞分泌Aβ是由结合GR后核转位介导的基因组效应介导的。
3.探讨了GC促进星形胶质细胞生成Aβ的分子机制。
用定量RT-PCR和Western blotting检测了地塞米松或者皮质酮处理星形胶质细胞后APP和BACE的表达变化。结果显示,星形胶质细胞中APP和BACE的mRNA和蛋白表达均升高,由BACE剪切APP产生的Aβ的前体蛋白C99的含量也升高。说明GC促进星形胶质细胞中APP和BACE的表达升高可能是引起Aβ分泌增加的原因。
4.发现了GC能够抑制星形胶质细胞吞噬和降解Aβ。
在体外培养的成年星形胶质细胞上,加入地塞米松后用激光共聚焦检测对Aβ1–42吞噬和降解的影响。结果显示,GC明显抑制星形胶质细胞吞噬和降解Aβ1–42的效率;而加入GR拮抗剂RU 38486几乎抵消了GC的效果,而MR拮抗剂RU 28318没有明显影响GC的效果。结果提示GC能够抑制星形胶质细胞吞噬和降解Aβ1–42,其效果是依赖于GR的。
5.体内实验进一步明确了GC影响星形胶质细胞Aβ代谢在AD病理中的作用。
分别选取5月龄和12月龄的正常和转基因AD小鼠,连续腹腔注射10 d地塞米松,并设立RU 38486拮抗组,观察GC对星形胶质细胞数量、APP及BACE表达和Aβ斑块形成的效应。结果发现:注射GC可以增加皮层和海马区星形胶质细胞数量,并且在AD小鼠中,大量星形胶质细胞包绕于蛋白斑周围。GC增加了Aβ斑块,证实了GC对体内Aβ病理的促进作用。而星形胶质细胞中APP和BACE表达明显升高,提示GC通过增加这二者的表达增加Aβ的分泌,可能是促进蛋白斑形成引起AD病理的机制之一。
综上,本研究首次发现GC可以影响星形胶质细胞的Aβ代谢,增加Aβ生成同时抑制其降解。我们的研究结果提示GC通过作用于星形胶质细胞促进蛋白斑形成,参与AD病理的发生发展。这一发现的意义在于不仅更加明确了GC作为重要的神经内分泌激素可引起和加重AD病变,是AD发生的危险因素,而且让我们从作用于星形胶质细胞的新途径认识了导致AD病理的机制。
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. The two hallmark neuropathological features are amyloidβ-peptide (Aβ) plaques and tau-laden neurofibrillary tangles. Although mutations in three different genes are known to underlie some cases of the rare, inheritable forms of the AD, the etiology of the more common sporadic cases remains unknown, and familial AD accounts for fewer than 10% of cases of AD and sporadic AD accounts for most case, it likely involves complex interactions between various genetic and environmental factors, such as a stressful lifestyle. Epidemiological evidence further supports a role for stress (such as a stressful lifestyle) as a risk factor for AD because elderly individuals prone to psychological distress are more likely to develop the disorder than age-matched, nonstressed individuals. Further, Aβlevels and amyloid plaque formation can be reduced by environmental enrichment, so it is important to investigate how environmental influences have an impact on and contribute to the pathogenesis of the disease.
Neuroendocrine malfunctions may be involved in the disease process, particularly because it is established that stress hormones can negatively affect neuronal survival. Environmental factors such as stress activate receptors includingβ-adrenergic receptors and d-opioid receptor. Aβproduction can be reduced by activation of the muscarinic acetylcholine receptor or estrogen receptor, somatostatin,β-adrenergic receptor. Even some of them can ameliorate amyloid plaque pathology.
Glucocorticoids (GC) are steroid hormones that readily cross the blood– brain barrier and bind to glucocorticoid receptors (GR). The glucocorticoid response to stressful stimuli is regulated by the hypothalamic–pituitary–adrenal (HPA) axis, which triggers the adrenal cortex to release GC (cortisol in primates, corticosterone in rodents). Activity of the receptor is crucial for many central nervous system (CNS) functions, including learning and memory. There is markedly elevated basal levels of circulating cortisol in AD, reflected by markedly elevated basal levels of circulating cortisol. Thus , GC as important neuroendocrine hormones in stress response have caused growing concern in the pathogenesis of AD.
Aβis a major constituent of senile plaque and is derived from the sequential proteolytic cleavage of amyloid precursor protein (APP) byβ-secretase (β-site APP cleaving enzyme, BACE) andγ-secretase. Accumulation of the Aβin the brain can lead to the formation of amyloid deposits and is crucial for development of AD. The process that regulates the deposition of Aβin the brain is still under investigation. A better understanding of the mechanism leading to Aβproduction would facilitate the development of treatments for AD. Several glucocorticoid-responsive elements (GRE) within the APP and BACE promoter have been identified and these sites occur in a region of the promoter that positively influences transcription. So whether GC can increase the production of Aβvia influencing the expression of APP and BACE?
An astrocytic gliosis and activation is always observed in brains of patients with AD. Although neurons are known to be the major source of Aβin AD, astrocytes, on the contrary, are known to be important for Aβclearance and degradation, for providing trophic support to neurons, and for forming a protective barrier between Aβdeposits and neurons. However, under certain conditions related to chronic stress, the role of astrocytes may not be beneficial. Studies have suggested that cultured astrocytes could generate modest amounts of Aβcompared with neurons. Recent work performed from transgenic mice (Tg2576) exhibiting amyloid plaques evidenced that astrocyte-derived Aβparticipate in plaque formation and maturation at later stages than neuronal Aβ. There is evidence demonstrating that astrocytes are an alternative source of BACE in animal models of chronic gliosis and in brains of AD patients and therefore may contribute to Aβplaque formation. And TGF-β1 has been confirmed to potentiate Aβproduction in human astrocytes and may enhance the formation of plaques burden in the brain of AD patients. These data led us to reconsider the participation of astrocytes in the amyloidogenic process. This would suggest that the mechanism for astrocytes play a role in the development of AD and that therapeutic strategies that target astrocyte activation in brain may be beneficial for the treatment of AD.
The present study sought to determine whether GC modulate the hallmark neuropathological feature of AD-Aβformation and degradation through astrocyte and, if so, the underlying mechanism. The results will suggest a mechanism by which GC in stress affects AD neuropathology. The main contents and results of the research including:
Firstly, we established the cell model of GC stimulate astrocytes. AdEASY adenovirus system was used to express APPSW mutant and wild type APP. Astrocytes infected with adenovirus were stimulated with dexamethasone or corticosterone (CORT). Unstimulated astrocytes secreted nearly no Aβ, but GC could trigger the Aβproduction in astrocytes, furthermore, the amounts of Aβwere correlated with the dose and time of treatment.
Secondly, we determined the underlying mechanisms of how GC promote Aβsecretion in astrocytes. We investigated GC have a role in the biological effects through genomic effect or non-genomic effect. Results showed that bovine serum albumin-corticosterone (BSA-CORT) had no effects on Aβsecretion in astrocytes. Furthermore, the effect of GC occurs through activation of the GR, as an antagonist of this receptor type RU 38486 prevents GC mediated increases in Aβ, and the GR is widely known to mediate transcription during agonist binding, dimerization, and relocation to the nucleus. So it suggested that GC increased Aβsecretion in astrocytes via GR-mediated genomic effect.
Thirdly, we investigated the levels of the BACE and its substrate APP in astrocytes after GC administration using real-time RT-PCR and Western blotting. Both the APP and BACE genes contain GC-response binding elements, making GC directly increase transcription of the APP and BACE genes, leading to the increased Aβproduction observed in astrocytes. Increases in APP and BACE proteins lead to increased processing of APP to C99 by BACE, which is consequently cleaved by theγ-secretase to release Aβ.
Fourthly, we detected whether GC treatment of astrocytes in culture impeded degradation of Aβpeptides, in which in vivo application resulted in more compact Aβplaques containing more of the peptide. Cofocal microscope results demonstrated that GC reduced clearance and degradation of Aβin astrocytes, and this effect was mediated by GR.
Fifthly, to study the link between elevated levels of stress hormones and AD genesis, we investigated the effects of GC on APP processing in astrocytes, as well as on the Aβburden in vivo. We found that GC increased the numbers of astrocytes both in cortex and hippocampus. And many GFAP+ astrocytes surrounded the Aβplaques. Consistent with stress being a risk factor for AD, we showed that administering GC to Tg-AD mice increased insoluble Aβload in both young and aged mice. Here we report the novel findings that levels of the BACE and its substrate APP in astrocytes are selectively increased after GC administration, resulting in increased production of Aβ.
In conclusion, the present study indicates the contribution of GC to AD pathology–Aβplaque formation by increasing generation and reducing clearance of Aβin astrocytes. Our findings provide support for the hypothesis that elevated GC found in AD play a significant causal role in the development of the pathology and highlight a mechanism by which stress affects AD neuropathology and suggest that stress warrant additional consideration in the regimen of AD therapies.
在众多的环境因素中,应激等精神心理因素如抑郁、焦虑等在神经退行性疾病发病中的作用日益受到重视。应激反应的基础是体内一系列神经-内分泌-免疫网络系统反应,应激相关的神经内分泌激素很可能是AD发生发展过程中重要的因素。糖皮质激素(Glucocorticoids,GC)属于类固醇激素,容易穿过血脑屏障结合糖皮质激素受体(Glucocorticoid Receptors, GR)。现已证实, GC对于中枢神经系统(Central Nervous System,CNS)的许多功能,包括学习和记忆都非常重要,但在应激中产生的过量GC会损害认知功能。GC对应激刺激的反应受下丘脑-垂体-肾上腺(Hypothalamic–Pituitary–Adrenal,HPA)轴的调控,由肾上腺皮质释放GC(灵长类是皮质醇,啮齿类是皮质酮)。流行病学调查表明AD病人中HPA轴功能失调,表现为循环水平的皮质醇水平显著升高。因此,GC作为应激反应中重要的神经内分泌激素很可能参与AD的发生发展。
在AD发病机理的研究方面,目前大多数学者都认为,大脑Aβ的代谢异常——包括过度产生或降解减少,引起Aβ聚合沉积形成β淀粉样蛋白斑在AD的发生发展中起关键作用。Aβ是淀粉样前体蛋白(amyloid precursor protein,APP)被β分泌酶(APP的β位点裂解酶,β-site APP cleaving enzyme,BACE)和γ分泌酶相继裂解的产物。以往对AD发病中Aβ代谢异常的研究主要集中于大脑的神经元,实验发现,GC可通过影响神经元Aβ代谢,从而对AD的发生发展起一定的促进作用。近年来,星形胶质细胞在AD发病中的重要作用越来越受到关注。研究表明,星形胶质细胞具有分泌和降解清除Aβ的双重功能。一方面,在对转基因AD小鼠和AD病人的研究中发现,星形胶质细胞来源的Aβ参与蛋白斑形成和成熟,只是在时相上晚于神经元。另一方面,对老年AD病人大脑的尸检分析,常可观察到Aβ斑块周围存在大量的星形胶质细胞,进一步的实验证实增生和活化的星形胶质细胞可以吞噬和降解Aβ。有资料显示:GC能调控星形胶质细胞的增殖、分化过程以及细胞因子的分泌,是神经退行性疾病中影响星形胶质细胞代谢的关键激素。但迄今为止,有关GC是否影响星形胶质细胞Aβ的代谢过程,参与AD的发病尚未见报道。
在本研究中,我们使用应激浓度的GC,通过体内外实验研究GC对星形胶质细胞Aβ代谢的效应和机制,以及对AD病理的影响。期望从星形胶质细胞调控Aβ代谢的新角度认识GC在AD发生发展中的作用,为深入理解散发性AD的发病机制提供新的理论依据,并为寻找有效防治靶点提供线索。
本文的主要研究内容及结果包括:
1.证实了GC能够促进星形胶质细胞生成Aβ。
建立了体外GC刺激星形胶质细胞分泌Aβ的模型:利用AdEASY腺病毒系统在293细胞成功表达了含APPSW突变型和APP野生型的腺病毒,用腺病毒感染原代星形胶质细胞后,加入地塞米松或者皮质酮检测对Aβ分泌的影响。结果显示,在未受刺激的条件下,星形胶质细胞基本不分泌Aβ,糖皮质激素可以促进星形胶质细胞分泌Aβ,并且和刺激剂量及时间呈正相关关系。
2.明确了GC促进星形胶质细胞生成Aβ的效应通路。
首先,检测了GC发挥作用是通过GC的基因组效应还是非基因组效应实现的。结果发现,用不可穿过胞膜的BSA偶联的皮质酮刺激星形胶质细胞无促进Aβ分泌的作用,说明GC的效应是通过基因组效应实现的。其次,检测了GC发挥基因组效应的受体通路。结果显示,GR的拮抗剂米非司酮(mifepristone,RU 38486)可以完全阻断GC促进星形胶质细胞分泌Aβ的作用,相反盐皮质激素受体(mineralocorticoid receptor,MR)的拮抗剂安体舒通(spironolactone,RU 28318)对GC该效应没有明显抑制,进一步说明GC促进星形胶质细胞分泌Aβ是由结合GR后核转位介导的基因组效应介导的。
3.探讨了GC促进星形胶质细胞生成Aβ的分子机制。
用定量RT-PCR和Western blotting检测了地塞米松或者皮质酮处理星形胶质细胞后APP和BACE的表达变化。结果显示,星形胶质细胞中APP和BACE的mRNA和蛋白表达均升高,由BACE剪切APP产生的Aβ的前体蛋白C99的含量也升高。说明GC促进星形胶质细胞中APP和BACE的表达升高可能是引起Aβ分泌增加的原因。
4.发现了GC能够抑制星形胶质细胞吞噬和降解Aβ。
在体外培养的成年星形胶质细胞上,加入地塞米松后用激光共聚焦检测对Aβ1–42吞噬和降解的影响。结果显示,GC明显抑制星形胶质细胞吞噬和降解Aβ1–42的效率;而加入GR拮抗剂RU 38486几乎抵消了GC的效果,而MR拮抗剂RU 28318没有明显影响GC的效果。结果提示GC能够抑制星形胶质细胞吞噬和降解Aβ1–42,其效果是依赖于GR的。
5.体内实验进一步明确了GC影响星形胶质细胞Aβ代谢在AD病理中的作用。
分别选取5月龄和12月龄的正常和转基因AD小鼠,连续腹腔注射10 d地塞米松,并设立RU 38486拮抗组,观察GC对星形胶质细胞数量、APP及BACE表达和Aβ斑块形成的效应。结果发现:注射GC可以增加皮层和海马区星形胶质细胞数量,并且在AD小鼠中,大量星形胶质细胞包绕于蛋白斑周围。GC增加了Aβ斑块,证实了GC对体内Aβ病理的促进作用。而星形胶质细胞中APP和BACE表达明显升高,提示GC通过增加这二者的表达增加Aβ的分泌,可能是促进蛋白斑形成引起AD病理的机制之一。
综上,本研究首次发现GC可以影响星形胶质细胞的Aβ代谢,增加Aβ生成同时抑制其降解。我们的研究结果提示GC通过作用于星形胶质细胞促进蛋白斑形成,参与AD病理的发生发展。这一发现的意义在于不仅更加明确了GC作为重要的神经内分泌激素可引起和加重AD病变,是AD发生的危险因素,而且让我们从作用于星形胶质细胞的新途径认识了导致AD病理的机制。
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. The two hallmark neuropathological features are amyloidβ-peptide (Aβ) plaques and tau-laden neurofibrillary tangles. Although mutations in three different genes are known to underlie some cases of the rare, inheritable forms of the AD, the etiology of the more common sporadic cases remains unknown, and familial AD accounts for fewer than 10% of cases of AD and sporadic AD accounts for most case, it likely involves complex interactions between various genetic and environmental factors, such as a stressful lifestyle. Epidemiological evidence further supports a role for stress (such as a stressful lifestyle) as a risk factor for AD because elderly individuals prone to psychological distress are more likely to develop the disorder than age-matched, nonstressed individuals. Further, Aβlevels and amyloid plaque formation can be reduced by environmental enrichment, so it is important to investigate how environmental influences have an impact on and contribute to the pathogenesis of the disease.
Neuroendocrine malfunctions may be involved in the disease process, particularly because it is established that stress hormones can negatively affect neuronal survival. Environmental factors such as stress activate receptors includingβ-adrenergic receptors and d-opioid receptor. Aβproduction can be reduced by activation of the muscarinic acetylcholine receptor or estrogen receptor, somatostatin,β-adrenergic receptor. Even some of them can ameliorate amyloid plaque pathology.
Glucocorticoids (GC) are steroid hormones that readily cross the blood– brain barrier and bind to glucocorticoid receptors (GR). The glucocorticoid response to stressful stimuli is regulated by the hypothalamic–pituitary–adrenal (HPA) axis, which triggers the adrenal cortex to release GC (cortisol in primates, corticosterone in rodents). Activity of the receptor is crucial for many central nervous system (CNS) functions, including learning and memory. There is markedly elevated basal levels of circulating cortisol in AD, reflected by markedly elevated basal levels of circulating cortisol. Thus , GC as important neuroendocrine hormones in stress response have caused growing concern in the pathogenesis of AD.
Aβis a major constituent of senile plaque and is derived from the sequential proteolytic cleavage of amyloid precursor protein (APP) byβ-secretase (β-site APP cleaving enzyme, BACE) andγ-secretase. Accumulation of the Aβin the brain can lead to the formation of amyloid deposits and is crucial for development of AD. The process that regulates the deposition of Aβin the brain is still under investigation. A better understanding of the mechanism leading to Aβproduction would facilitate the development of treatments for AD. Several glucocorticoid-responsive elements (GRE) within the APP and BACE promoter have been identified and these sites occur in a region of the promoter that positively influences transcription. So whether GC can increase the production of Aβvia influencing the expression of APP and BACE?
An astrocytic gliosis and activation is always observed in brains of patients with AD. Although neurons are known to be the major source of Aβin AD, astrocytes, on the contrary, are known to be important for Aβclearance and degradation, for providing trophic support to neurons, and for forming a protective barrier between Aβdeposits and neurons. However, under certain conditions related to chronic stress, the role of astrocytes may not be beneficial. Studies have suggested that cultured astrocytes could generate modest amounts of Aβcompared with neurons. Recent work performed from transgenic mice (Tg2576) exhibiting amyloid plaques evidenced that astrocyte-derived Aβparticipate in plaque formation and maturation at later stages than neuronal Aβ. There is evidence demonstrating that astrocytes are an alternative source of BACE in animal models of chronic gliosis and in brains of AD patients and therefore may contribute to Aβplaque formation. And TGF-β1 has been confirmed to potentiate Aβproduction in human astrocytes and may enhance the formation of plaques burden in the brain of AD patients. These data led us to reconsider the participation of astrocytes in the amyloidogenic process. This would suggest that the mechanism for astrocytes play a role in the development of AD and that therapeutic strategies that target astrocyte activation in brain may be beneficial for the treatment of AD.
The present study sought to determine whether GC modulate the hallmark neuropathological feature of AD-Aβformation and degradation through astrocyte and, if so, the underlying mechanism. The results will suggest a mechanism by which GC in stress affects AD neuropathology. The main contents and results of the research including:
Firstly, we established the cell model of GC stimulate astrocytes. AdEASY adenovirus system was used to express APPSW mutant and wild type APP. Astrocytes infected with adenovirus were stimulated with dexamethasone or corticosterone (CORT). Unstimulated astrocytes secreted nearly no Aβ, but GC could trigger the Aβproduction in astrocytes, furthermore, the amounts of Aβwere correlated with the dose and time of treatment.
Secondly, we determined the underlying mechanisms of how GC promote Aβsecretion in astrocytes. We investigated GC have a role in the biological effects through genomic effect or non-genomic effect. Results showed that bovine serum albumin-corticosterone (BSA-CORT) had no effects on Aβsecretion in astrocytes. Furthermore, the effect of GC occurs through activation of the GR, as an antagonist of this receptor type RU 38486 prevents GC mediated increases in Aβ, and the GR is widely known to mediate transcription during agonist binding, dimerization, and relocation to the nucleus. So it suggested that GC increased Aβsecretion in astrocytes via GR-mediated genomic effect.
Thirdly, we investigated the levels of the BACE and its substrate APP in astrocytes after GC administration using real-time RT-PCR and Western blotting. Both the APP and BACE genes contain GC-response binding elements, making GC directly increase transcription of the APP and BACE genes, leading to the increased Aβproduction observed in astrocytes. Increases in APP and BACE proteins lead to increased processing of APP to C99 by BACE, which is consequently cleaved by theγ-secretase to release Aβ.
Fourthly, we detected whether GC treatment of astrocytes in culture impeded degradation of Aβpeptides, in which in vivo application resulted in more compact Aβplaques containing more of the peptide. Cofocal microscope results demonstrated that GC reduced clearance and degradation of Aβin astrocytes, and this effect was mediated by GR.
Fifthly, to study the link between elevated levels of stress hormones and AD genesis, we investigated the effects of GC on APP processing in astrocytes, as well as on the Aβburden in vivo. We found that GC increased the numbers of astrocytes both in cortex and hippocampus. And many GFAP+ astrocytes surrounded the Aβplaques. Consistent with stress being a risk factor for AD, we showed that administering GC to Tg-AD mice increased insoluble Aβload in both young and aged mice. Here we report the novel findings that levels of the BACE and its substrate APP in astrocytes are selectively increased after GC administration, resulting in increased production of Aβ.
In conclusion, the present study indicates the contribution of GC to AD pathology–Aβplaque formation by increasing generation and reducing clearance of Aβin astrocytes. Our findings provide support for the hypothesis that elevated GC found in AD play a significant causal role in the development of the pathology and highlight a mechanism by which stress affects AD neuropathology and suggest that stress warrant additional consideration in the regimen of AD therapies.
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