阿尔茨海默病APPswe/PS1dE9双转基因小鼠的病理生化和行为学研究(英文)

目的阿尔茨海默病(Alzheimer’sdisease,AD)APPswe/PS1dE9双转基因小鼠已被广泛运用于各种实验研究。AD小鼠脑内产生过量的β淀粉样蛋白(Aβ),后者会影响突触功能和中枢神经系统的发育。然而,该转基因小鼠模型的生化和行为学特征却未见报道。本研究旨在对该小鼠模型的病理从生化和行为学角度进行检测。方法对6月和12月龄转基因和野生型小鼠取血约100μL,1200g离心后,分离血清。在小鼠6月和12月龄时,进行为期15天的辐射状六臂水迷宫实验。ELISA法检测血清和大脑中Aβ1-40和Aβ1-42的含量,以及血清中8-羟基脱氧鸟苷的含量。比较转基因和野生型小鼠大脑不同部位中α-,β-和γ-分泌酶活性的差异。结果在6月龄之前,APP-swe/PS1dE9双转基因小鼠的死亡率约为35%,这些死亡的小鼠脑内Aβ1-40和Aβ1-42水平较高,两者比例约为1:10。在6月和12月龄时,转基因小鼠血清中Aβ1-40水平均显著高于Aβ1-42水平,Aβ1-40与Aβ1-42比例为2.37:1。在12月龄时,转基因小鼠大脑中Aβ1-42水平显著高于Aβ1-40水平,两者比例约为2.17:1,并且在不同脑区中,Aβ1-42和Aβ1-40含量变化较大。在小脑、前、后部皮质层以及海马中,Aβ1-42水平显著高于Aβ1-40。分泌酶活性在转基因和野生型小鼠之间以及在不同脑部位之间没有很大的差异,这提示PS1转基因并没有导致高γ-分泌酶活性,该基因可能使γ-分泌酶更有效的切割和产生Aβ1-42。此外,转基因小鼠血清中8-羟基脱氧鸟苷含量较野生型小鼠升高,但没有显著性差异。行为学结果显示,在6月龄时,转基因小鼠与野生型相比呈现出显著的记忆障碍,到12月龄时,这种障碍变得更为严重,表现为水迷宫实验中产生更多的错误。结论 APPswe/PS1dE9双转基因小鼠最早在6月龄时就能很好地模拟早发性AD,可用于实验研究。     

阿尔茨海默病APPswe/PS1dE9双转基因小鼠的病理生化和行为学研究(英文)

目的阿尔茨海默病(Alzheimer’sdisease,AD)APPswe/PS1dE9双转基因小鼠已被广泛运用于各种实验研究。AD小鼠脑内产生过量的β淀粉样蛋白(Aβ),后者会影响突触功能和中枢神经系统的发育。然而,该转基因小鼠模型的生化和行为学特征却未见报道。本研究旨在对该小鼠模型的病理从生化和行为学角度进行检测。方法对6月和12月龄转基因和野生型小鼠取血约100μL,1200g离心后,分离血清。在小鼠6月和12月龄时,进行为期15天的辐射状六臂水迷宫实验。ELISA法检测血清和大脑中Aβ1-40和Aβ1-42的含量,以及血清中8-羟基脱氧鸟苷的含量。比较转基因和野生型小鼠大脑不同部位中α-,β-和γ-分泌酶活性的差异。结果在6月龄之前,APP-swe/PS1dE9双转基因小鼠的死亡率约为35%,这些死亡的小鼠脑内Aβ1-40和Aβ1-42水平较高,两者比例约为1:10。在6月和12月龄时,转基因小鼠血清中Aβ1-40水平均显著高于Aβ1-42水平,Aβ1-40与Aβ1-42比例为2.37:1。在12月龄时,转基因小鼠大脑中Aβ1-42水平显著高于Aβ1-40水平,两者比例约为2.17:1,并且在不同脑区...     

《卒中与神经疾病》2007年第14卷关键词索引

(按关键词汉语拼音字母顺序排列,未译出的英文及缩略词按首字母列入)AADAM10α-分泌酶ADAM10对APP转基因小鼠情绪和学习行为的影响(张玲,林燕)(5):283APPα-分泌酶ADAM10对APP转基因小鼠情绪和学习行为的影响(张玲,林燕)(5):283A型肉毒毒素长期重复应用A型肉毒毒素治疗面肌痉挛对面神经传导速度及CMAP的影响(韩旺,秦晓凌,罗蔚锋等)(2):105α-分泌酶(ADAM17)脑慢性低灌注老龄大鼠海马ε型蛋白激酶C及α分泌酶AD-AM17表达的变化(周燕,闫福岭)(6):330阿尔茨海默病灵芝多糖对模拟AD学习记忆障碍大鼠海马白细胞介素-6表达的影响(…     

丹参酮对β-淀粉样肽致拟痴呆小鼠的保护作用及机制

目的探讨丹参酮对β-淀粉样肽（A13）致拟痴呆小鼠（AD小鼠）的保护作用及机制。方法利用单侧脑室一次性注射可溶性大片段Aβ1-42复制拟痴呆动物模型，将小鼠随机分为对照组，模型组、脑复康（200mg／kg）组及丹参酮（20、40、80mg／kg）组。通过避暗实验和Morris水迷宫实验观察丹参酮对AD小鼠学习记忆能力的影响及血清、脑、肝脏内SOD、MDA含量和皮层和海马中AChE、NO含量的变化。结果脑室内注射Aβ1-42后小鼠出现学习记忆障碍；血清、脑、肝中SOD活性降低、MDA含量增加；大脑皮层、海马组织中AChE、NO含量上升；应用丹参酮后AD小鼠学习记忆能力提高，丹参酮组中、高剂量组抑制了血清、脑、肝中SOD活性的降低和MDA含量的增加（P〈0．01，0．001），亦减少大脑皮层、海马组织中AChE、NO的生成（P〈0．05，0．01，0．001）。结论丹参酮对β-淀粉样肽致拟痴呆小鼠具有一定的保护作用，其机制可能与抗氧化、抑制AChE生成有关。     

白藜芦醇对β-淀粉样蛋白致小鼠学习记忆障碍改善作用的机制研究

目的探讨白藜芦醇改善阿尔茨海默病(Alzheimer’s disease,AD)动物模型学习记忆障碍的作用机制。方法本实验采用45只小鼠侧脑室注射Aβ1-42建立AD模型,随机分为假手术组、模型组、白藜芦醇给药组。Morris水迷宫试验观察大鼠学习记忆能力的变化,尼氏染色观察大鼠海马神经元结构变化,ELISA检测大鼠海马组织中TNF-α和IL-1β的含量。结果 Aβ1-42侧脑室注射可造成小鼠明显的学习记忆功能障碍和海马神经元的大量丢失,并可导致海马区TNF-α和IL-1β产生量明显增加和NF-κB炎症信号通路激活,引起炎症反应。小鼠灌胃给予白藜芦醇后可明显改善其学习记忆功能障碍(P<0.05)和提高海马神经元的数量(P<0.05),显著抑制TNF-α(P<0.01)和IL-1β(P<0.05)产生量和NF-κB(P<0.05)炎症信号通路的激活。结论白藜芦醇对AD具有治疗作用,其作用机制可能与抑制炎症反应,进而保护神经元有关。     

α-分泌酶ADAM10对APP转基因小鼠情绪和学习行为的影响

目的探讨α-分泌酶ADAM10对阿尔茨海默病发生的作用。方法采用开场实验、高架十字迷宫和水迷宫实验测试并比较APP转基因小鼠和APP/ADAM10双转基因小鼠的行为学差异。结果与对照组小鼠相比,APP转基因小鼠焦虑性增高,自主活动力减弱,空间学习记忆力下降,差异有显著性(P<0.05);而APP/ADAM10双转基因小鼠各种行为和对照组相比无显著性差异(P>0.05)。结论α-分泌酶ADAM10能显著改善小鼠的情绪,提高APP转基因小鼠的自主活动力和学习、记忆能力,开发激活AD-AM10酶活性的药物或者在神经细胞表达ADAM10可望成为治疗阿尔茨海默病的新途径。     

基质细胞衍生因子-1对阿尔茨海默病脑内可溶性Aβ清除作用的研究

目的通过对APP/PS1双转基因小鼠侧脑室持续注射基质细胞衍生因子-1(SDF-1),以观察SDF-1对脑内可溶性β淀粉样蛋白(Aβ)的影响及其可能的机制。方法将28周龄的野生型(wild type,WT)小鼠和APP/PS1转基因小鼠分为对照组和SDF-1α干预组,分别予以侧脑室注射SDF-1α和PBS,1周1次,连续注射4周和8周。采用ELISA法检测小鼠脑内可溶性Aβ的水平,采用Wsetern blot方法检测小鼠脑内小胶质细胞标志物Iba-1的水平。结果 SDF-1α侧脑室注射后APP/PS1小鼠脑内可溶性Aβ-40和Aβ-42水平与对照组相比明显减少,APP/PS1小鼠及WT小鼠脑内Iba-1水平较对照组增加。结论 SDF-1α侧脑室注射可能减少APP/PS1小鼠脑内可溶性Aβ的水平,其作用的机制可能是SDF-1α增加了脑内小胶质细胞由外周向中枢的募集,从而促进Aβ的吞噬清除。动员与趋化骨髓来源的小胶质细胞可能成为治疗AD的新靶点。     

阿尔茨海默病APPswe/PS1dE9双转基因型与野生型小鼠学习记忆能力的比较

目的：比较不同年龄段阿尔茨海默病（AD）APPswe/PS1dE9双转基因型与野生型小鼠的学习记忆能力。方法：C57BL/6J雌鼠与C3H/HeJ雄鼠交配产下F1代,再将F1代与3月龄的APPswe/PS1dE9双转基因型小鼠交配产下F2代。提取F2代小鼠鼠尾DNA,PCR扩增目的基因并鉴定。依据是否含APP和PS1基因分为转基因型组和野生型对照组,小鼠分别于6、8月龄行Morris水迷宫实验,11月龄行Y迷宫实验检测学习记忆能力。结果：繁育F2代小鼠33只,其中转基因型组18只,野生型对照组15只。6月龄转基因型与野生型小鼠定位航行实验潜伏期的差异无统计学意义,空间探索实验目标象限时间和路程百分比的差异无统计学意义（P〉0.05）。与8月龄野生型小鼠比较,转基因型小鼠定位航行实验第1天潜伏期延长（P〈0.05）。与11月龄野生型小鼠比较,转基因型小鼠达到学会标准的训练次数增加（P〈0.05）。结论：ADAPPswe/PS1dE9双转基因型与野生型小鼠比较,于11月龄时出现学习记忆能力障碍。     

姜黄素对阿尔茨海默病模型小鼠脑内胶质细胞介导的炎症反应的抑制作用

目的探讨姜黄素对AD模型小鼠学习记忆能力的影响。方法将80小鼠按随机原则分四组,对照组、Alcl3组、溶剂组及姜黄素组。Alcl3制作小鼠AD模型,之后给予腹腔注射姜黄素3 d,给药后14 d水迷宫测试学习记忆能力。免疫染色及western blot方法检测Aβ42、GFAP和Iba-1β蛋白水平。ELISA方法检测海马区炎症因子IL-1β,IL-6和TNF-α的水平。结果与对照组比,Alcl3能够导致逃避潜伏期延长和记忆下降更明显,说明AD模型成功建立。与Alcl3组和溶剂治疗组相比,姜黄素组明显减少潜伏期及增加穿越次数,而且显著减少Aβ42表达。相比Alcl3组,姜黄素组的GFAP和Iba-1β以及海马区IL-1β、IL-6及TNF-α的指标下降有显著意义。结论研究表明姜黄素有潜在治疗AD的可能,通过下调Alcl致胶质细胞过度活化引起炎症反应,而提高学习记忆能力。     

灵芝多糖对模拟AD学习记忆障碍大鼠海马白细胞介素-6表达的影响

目的 研究灵芝多糖对模拟AD学习记忆障碍大鼠脑组织白细胞介素-6表达（IL-6）的影响。方法 采用双侧海马内一次性注射β-淀粉样多肽25～35片段（Aβ25～35）制作模拟AD学习记忆障碍大鼠模型，造模24h后治疗组腹腔注射灵芝多糖注射液，其余各组分别注射等量的生理盐水，1次/d，疗程7d，并于第8d开始进行Morris水迷宫实验观察其学习记忆能力，行为学检测后再通过免疫组化SABC法检测各组大鼠海马IL-6表达水平。结果 模型组大鼠较对照组学习记忆能力降低，海马IL-6表达明显增强；治疗组大鼠较模型组学习记忆能力显著提高，海马IL-6表达显著下调。结论 灵芝多糖可提高Aβ25-35诱导的模拟AD学习记忆障碍大鼠的学习记忆能力，抑制海马IL-6表达。     

Apicidin attenuates memory deficits by reducing the Aβ load in APP/PS1 mice

Aims

Amyloid beta (Aβ) is an important pathological feature of Alzheimer's disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aβ by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aβ in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10.

Methods

Nine-month-old APP/PS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aβ levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting.

Results

Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aβ-enriched plaques, and decreased the levels of soluble and insoluble Aβ40/42 in APP/PS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPβ, but did not affect the levels of phosphorylated tau in APP/PS1 mice.

Conclusion

Apicidin significantly improves the AD symptoms of APP/PS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aβ rather than decreasing the phosphorylation of tau.     

Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation

Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by learning and memory function deterioration. While it is well established that exercise can improve cognitive performance in AD, there have been few basic cellular and molecular mechanisms research performed to test the interaction between exercise and AD. In this study, we aimed at investigating whether treadmill exercise improves learning and memory function in APP/PS1 transgenic mouse model of Alzheimer's disease by enhancing long-term potentiation (LTP) and up-regulation of brain-derived neurotrophic factor (BDNF) mRNA expression. Our results show that, in comparison to wild type mice, transgenic mice were characterized by impaired learning and memory function, LTP deficits and increased BDNF mRNA levels. Treadmill exercise enhanced learning and memory function not only in wild type mice but also in APP/PS1 mice paralleled by LTP. However, BDNF has emerged as a crucial regulator of synaptic plasticity mechanisms underlying learning and memory in wild-type mice, but not in APP/PS1 mice. Hence, this investigation demonstrates that treadmill exercise is an effective therapeutic that alleviate learning and memory decline in APP/PS1 mouse model, and enhanced LTP maybe a cellular mechanism involved in neuropathological course of AD and cognitive improvement induced by exercise.     

Insulin-Like Growth Factor-1 Alleviates Expression of Aβ<Subscript>1–40</Subscript> and α-, β-, and γ-Secretases in the Cortex and Hippocampus of APP/PS1 Double Transgenic Mice

To examine the effect of subcutaneous injection of insulin-like growth factor-1 (IGF-1) on the expression of the amyloid protein (Aβ_1–40), α-secretase (ADAM10), β-secretase (BACE1), and γ-secretase (PS1) in APP/PS1 double transgenic mice. APP/PS1 double transgenic mice and wild-type mice were divided into wild-type group, wild-type therapy group, transgenome group, and transgenic therapy group. Subcutaneous injection of IGF-1 (50 μg/kg day) was administered once daily to the wild-type therapy group and transgenic therapy group for 8 weeks, respectively. The expression of the Aβ_1–40 in the cortex and hippocampus was detected by immunohistochemistry 8 weeks after administration. The levels of Aβ_1–40, DAM10, BACE1, and PS1 were analysed by Western blot. The expression of the Aβ_1–40 in the cortex of the gene therapy group was significantly lower than that of the transgenome group (p?<?0.05). In APP/PS1 double transgenic mice, BACE1 expression was markedly higher in both the hippocampus (p?<?0.001, p?=?0.00009) and the cortex (p?=?0.001), compared to that of the wild-type mice. The treatment of IGF-1 markedly reduced ADAM10 expression in the hippocampus in both transgenic mice and wild-type mice (p?<?0.05), whereas the treatment mainly decreased BACE1 expression in transgenic mice but not in the wild-type mice (p?<?0.05). No significant differences in PS1 levels were detected in all groups. IGF decreased Aβ_1–40 over-expression in the cortex and hippocampus and might inhibit the damage induced by Aβ_1–40 in APP/PS1 double transgenic mice. Our study suggests that IGF-1 should inhibit Aβ production through α-secretase and β-secretase but not γ-secretase.     

APP/PS1双转基因小鼠早期记忆功能障碍与胆碱能系统的关系研究

目的观察转APP/PS1基因阿尔茨海默病小鼠(APP/PS1小鼠)早期空间学习记忆功能及乙酰胆碱能系统的变化以及两者之间的相关性,探讨阿尔茨海默病早期学习记忆障碍的发病机制。方法应用Morris水迷宫法评定3月龄APP/PS1小鼠及相应野生型(WT)小鼠的空间学习记忆功能;采用免疫组织化学及组织化学染色方法检测脑组织中β-淀粉样蛋白(Aβ)斑块沉积情况;采用ELISA法检测脑组织中乙酰胆碱(ACh)含量以及胆碱乙酰转移酶(ChAT)和乙酰胆碱酯酶(AChE)活性,并探讨小鼠脑组织中ACh含量与其空间记忆能力、ChAT活性的相关性。结果水迷宫评定结果显示两组小鼠到达平台的潜伏期无统计学差异(P>0.05);APP/PS1小鼠在目标象限的游泳时间百分比〔(29.02±4.27)%〕和距离百分比〔(28.85±3.77)%〕较WT小鼠均下降(P<0.05)。APP/PS1小鼠脑组织中尚无Aβ斑块的沉积。APP/PS1小鼠脑组织中ACh含量〔(45.23±1.40)ng/g prot〕和ChAT活性〔(279.53±12.13)U/g组织湿重〕均较WT小鼠〔分别为(54.08±4.84)ng/gprot、(315.84±11.32)U/g组织湿重〕显著降低(P<0.05),两组小鼠脑组织中AChE活性无统计学差异(P>0.05)。小鼠脑组织中ACh含量与其空间记忆功能(目标象限航行时间百分比、目标象限航行路程百分比)呈正相关(r=0.861、r=0.874,P<0.05),ACh含量与ChAT活性呈正相关(r=0.926,P<0.05)。结论 APP/PS1小鼠空间记忆功能障碍、ACh含量减少和ChAT活性降低可发生于Aβ斑块沉积之前。脑组织中ACh含量减少和ChAT活性降低可能与APP/PS1小鼠记忆功能损害密切相关。     

Impaired Performance of Female APP/PS1 Mice in the Morris Water Maze Is Coupled with Increased Aβ Accumulation and Microglial Activation

Background: Alzheimer's disease (AD) is characterized by progressive neuronal loss and cognitive decline. Epidemiological studies suggest that the risk of AD is higher in women even when data are adjusted for age. Objective: We set out to compare changes in 9-month-old male and female mice which overexpress amyloid precursor protein (APP) with presenilin (PS1; APP/PS1 mice) and to evaluate whether any changes were coupled with deficits in spatial learning. Methods: APP/PS1 mice were assessed for their ability to learn in the Morris water maze and Aβ burden assessed by Congo Red and Aβ triple ultrasensitive assay. Neuroinflammatory changes were examined in brain tissue along with expression of Aβ-generating and Aβ-degrading enzymes. Results: A deficit in reversal phase learning in the Morris water maze was observed in female mice and was paralleled by evidence of increased accumulation of Aβ, microglial activation and expression of IL-1β. Accumulation of Aβ was coupled with an increase in expression of BACE-1 and a decrease in insulin-degrading enzyme (IDE). Conclusion: The results indicate that the observed impairment in spatial memory in female APP/PS1 mice correlated with increased Aβ burden and the changes in Aβ may have occurred as a result of enhanced BACE-1 and decreased IDE expression.     

阿尔茨海默病的干预与α分泌酶ADAM10

阿尔茨海默病（Alzheimer＇s Disease, AD）是老年人最常见的神经变性疾病.整合素和金属蛋白酶10（ADAM10）是一种α分泌酶,也是淀粉样前体蛋白（APP）的代谢中的一种关键蛋白酶,在AD中具有重要作用.在过表达ADAM10的动物模型中发现这种金属蛋白酶可以促进学习记忆和突触生成.因此,ADAM10在神经退行性病（如AD）中是一个有价值的靶点.ADAM10有很多底物,其中以APP最为显著.因此在治疗性提高ADAM10α分泌酶活性时任何副作用都要纳入考虑的范畴.这篇综述总结了目前有关ADAM10的结构和功能的信息,并进一步探讨提高α分泌酶的表达和/或活性作为治疗靶点的可能性.     

Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking

α-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer's disease (AD). Proteases similar to α-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid β peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β- and γ-secretase. In contrast, α-secretase, which is the metalloprotease ADAM10, cleaves APP within the Aβ domain, thus preventing Aβ generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in α-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating α-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage.     

Transauricular Vagal Nerve Stimulation at 40 Hz Inhibits Hippocampal P2X7R/NLRP3/Caspase-1 Signaling and Improves Spatial Learning and Memory in 6-Month-Old APP/PS1 Mice

ObjectivesTransauricular vagal nerve stimulation (taVNS) at 40 Hz attenuates hippocampal amyloid load in 6-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, but it is unclear whether 40-Hz taVNS can improve cognition in these mice. Moreover, the underlying mechanisms are still unclear.Materials and Methods6-month-old C57BL/6 (wild type [WT]) and APP/PS1 mice were subjected to 40-Hz taVNS. Novel Object Recognition and the Morris Water Maze were used to evaluate cognition. Hippocampal amyloid-β (Aβ)1-40, Aβ1-42, pro–interleukin (IL)-1β, and pro–IL-18 were measured using enzyme-linked immunosorbent assays. Hippocampal Aβ42, purinergic 2X7 receptor (P2X7R), nucleotide-binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3), Caspase-1, IL-1β, and IL-18 expression were evaluated by western blotting. Histologic assessments including immunofluorescence, immunohistochemistry, Nissl staining, and Congo red staining were used to assess microglial phagocytosis, neuroprotective effects, and Aβ plaque load.Results40-Hz taVNS improved spatial memory and learning in 6-month-old APP/PS1 mice but did not affect recognition memory. There were no effects on the cognitive behaviors of 6-month-old WT mice. taVNS at 40 Hz modulated microglia; significantly decreased levels of Aβ1-40, Aβ1-42, pro–IL-1β, and pro–IL-18; inhibited Aβ42, P2X7R, NLRP3, Caspase-1, IL-1β, and IL-18 expression; reduced Aβ deposits; and had neuroprotective effects in the hippocampus of 6-month-old APP/PS1 mice. These changes were not observed in 6-month-old WT mice.ConclusionOur results show that 40-Hz taVNS inhibits the hippocampal P2X7R/NLRP3/Caspase-1 signaling and improves spatial learning and memory in 6-month-old APP/PS1 mice.     

Circular HDAC9/microRNA-138/Sirtuin-1 Pathway Mediates Synaptic and Amyloid Precursor Protein Processing Deficits in Alzheimer's Disease

Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer's disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ RNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of mi R-138 in APP/PS1(presenilin-1) mice. Mi R-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta(Ab) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1(Sirt1), a target of mi R-138, ameliorated the mi R-138-induced inhibition of ADAM10 and elevation of Ab in vitro. The circ RNA HDAC9(circ HDAC9) was predicted to contain a mi R-138 binding site in several databases. Its expression was inversely correlated with mi R-138 in both Ab-oligomertreated N2 a cells and APP/PS1 mice, and it co-localized with mi R-138 in the cytoplasm of N2 a cells. Circ HDAC9 acted as a mi R-138 sponge, decreasing mi R-138 expression, and reversing the Sirt1 suppression and excessive Ab production induced by mi R-138 in vitro. Moreover,circ HDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment.These results suggest that the circ HDAC9/mi R-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.