• 【三种阿尔茨海默病转基因小鼠模型的睡眠和脑电图功率谱分析: APP/PS1,3xTgAD和tg2576。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-180260 复制DOI
    作者列表:Kent BA,Strittmatter SM,Nygaard HB
    BACKGROUND & AIMS: BACKGROUND:Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. OBJECTIVE:We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. METHODS:Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. RESULTS:Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. CONCLUSION:Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.
    背景与目标:
  • 【在阿尔茨海默氏病的3xtgad小鼠模型中,选择性地损害了在什么地方发生的类似情景的记忆。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-2012-121543 复制DOI
    作者列表:Davis KE,Easton A,Eacott MJ,Gigg J
    BACKGROUND & AIMS: :Episodic memory loss is a defining feature of early-stage Alzheimer's disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three-component task that can be solved without reliance on episodic recall (What-Where-When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, whereas, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non-episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model.
    背景与目标: : 偶发性记忆丧失是早期阿尔茨海默氏病 (AD) 的一个决定性特征。对rat的类似情景记忆的测试,即What-Where-whit场合任务 (wwwhit),需要将对象,位置和上下文信息关联起来,以形成事件的集成记忆。Wwwhit任务无法通过使用非情节信息 (例如对象熟悉度) 来解决,并且取决于海马的完整性。因此,它提供了一种理想的工具,可以用来测试AD的3xTg鼠模型中类似情节的记忆能力。由于该模型捕获了许多人类AD表型,因此我们假设这些小鼠在www中会显示出类似情节的记忆任务的缺陷。为了测试任何情节样缺陷的特异性,我们还检查了小鼠是否可以执行不需要情节样记忆的wwwhat任务的组成部分。其中包括对象 (新颖的对象识别),位置 (对象位置任务,What-Where任务) 和上下文 (What-Where) 记忆,以及另一个无需依赖情节回忆即可解决的三部分任务 (What-Where; Wwwhy)。结果首次表明,对照129sv/c57bl6小鼠可以形成情节样记忆,而6个月大的3xTgAD小鼠则受到损害。重要的是,虽然3xTgAD小鼠在空间组件任务上显示出一些缺陷,但它们在更复杂的wwiw组合任务 (包括空间组件,并且对非偶发解决方案开放) 中并未受到损害。这些结果强烈表明,以海马结构为中心的AD病理在3xtgad模型中介导了www的特定缺陷,即情景样记忆。
  • 【高脂饮食诱导的三重转基因阿尔茨海默氏病 (3xtgad) 小鼠的记忆障碍与淀粉样蛋白和tau病理的变化无关。】 复制标题 收藏 收藏
    DOI:10.1016/j.neurobiolaging.2014.02.010 复制DOI
    作者列表:Knight EM,Martins IV,Gümüsgöz S,Allan SM,Lawrence CB
    BACKGROUND & AIMS: :Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice.
    背景与目标: : 众所周知,肥胖和高脂饮食会增加患阿尔茨海默氏病 (AD) 的风险。高脂肪饮食还会增加AD小鼠模型的疾病神经病理学和/或认知缺陷。然而,在AD (3xTgAD) 的三重转基因小鼠模型中,高脂饮食对神经病理学和记忆障碍的影响尚不清楚。因此,将2个月大的雄性3xtgad和对照组 (非Tg) 小鼠维持高脂或对照饮食,并在3-4、7-8、11-12岁时评估记忆力,15-16个月使用一系列行为测试。在所有测试年龄的高脂喂养后,在非Tg和3xtgad小鼠中观察到体重的可比增加,但在7-8岁的3xtgad小鼠中观察到附睾脂肪组织的显着增加,11-12和15-16个月。高脂饮食早在3-4个月大时就导致非Tg对照小鼠的记忆力障碍。在3xtgad小鼠中,高脂肪消耗导致发病年龄的减少和记忆障碍程度的增加。高脂饮食对非Tg和3xtgad小鼠认知的某些影响是短暂的,检测到认知障碍的年龄取决于行为测试。高脂饮食对3xtgad小鼠记忆的影响与AD神经病理学的变化无关,因为未观察到 (斑块,低聚物) 或tau神经病理学的显着差异。在3-4个月大时,高脂喂养的3xTgAD小鼠中观察到小胶质细胞活化的急性增加,但在非Tg对照小鼠中,直到15-16个月大时才观察到小胶质细胞活化。因此,这些数据表明,高脂饮食对与神经炎症相关的对照组和AD小鼠的记忆具有快速而持久的负面影响,但与AD小鼠的 β 淀粉样蛋白和tau神经病理学的变化无关。
  • 【KATP通道激活剂二氮嗪改善了阿尔茨海默氏病3xtgad小鼠模型中的淀粉样 β 和tau病变并改善了记忆。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-2010-101017 复制DOI
    作者列表:Liu D,Pitta M,Lee JH,Ray B,Lahiri DK,Furukawa K,Mughal M,Jiang H,Villarreal J,Cutler RG,Greig NH,Mattson MP
    BACKGROUND & AIMS: :Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. Plasma and mitochondrial membrane potentials, cell excitability, intracellular Ca2+ levels and bioenergetics were measured in cultured cerebral cortical neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of Aβ oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD.
    背景与目标: : 受损的细胞能量代谢,脑灌注不足和神经元钙失调参与了阿尔茨海默氏病 (AD) 的病理过程。质膜和线粒体内膜中的ATP敏感性钾 (KATP) 通道在调节神经元兴奋性,细胞存活和脑血管张力中起重要作用。为了研究激活AD中KATP通道的药物的治疗潜力,我们首先表征了KATP通道开放剂二氮嗪对培养的神经元的作用,然后在AD的3xtgad小鼠模型中确定了其改变疾病过程的能力。在暴露于二氮嗪的培养的大脑皮层神经元中测量了血浆和线粒体膜电位,细胞兴奋性,细胞内Ca2水平和生物能学。二氮嗪超极化神经元,降低了动作电位的频率,减弱了通过NMDA受体通道的Ca2内流,并降低了氧化应激。用二氮嗪治疗8个月的3xtgad小鼠在学习和记忆测试中表现出改善的表现,降低了焦虑水平,减少了皮质和海马中a β 低聚物和过度磷酸化tau的积累,并增加了脑血流量。我们的发现表明,二氮嗪可以改善AD小鼠模型中的分子,细胞病理学和行为改变,这表明在AD治疗中激活KATP通道的药物具有治疗潜力。
  • 【阿尔茨海默氏病3xtgad小鼠模型中海马子区域的TSPO和淀粉样蛋白沉积。】 复制标题 收藏 收藏
    DOI:10.1016/j.nbd.2018.09.022 复制DOI
    作者列表:Tournier BB,Tsartsalis S,Rigaud D,Fossey C,Cailly T,Fabis F,Pham T,Grégoire MC,Kövari E,Moulin-Sallanon M,Savioz A,Millet P
    BACKGROUND & AIMS: :The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [125I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [125I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APPSWE, PS1M146V and TauP301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.
    背景与目标: : 18kDa转运蛋白 (TSPO) (神经炎症的标志物) 在阿尔茨海默氏病 (AD) 中的参与仍存在争议。在本报告中,我们使用了 [125I]-CLINDE,这是一种以前从未在AD中使用过的SPECT TSPO放射性示踪剂,并且我们在AD的三重转基因小鼠模型中研究了TSPO与淀粉样斑块密度之间的关系 (使用 [125I]-DRM106) (3xTgAD,APPSWE,PS1M146V和TauP301L)。我们的结果表明,TSPO增加出现在淀粉样蛋白沉积之前。此外,海马的不同部分受到不同程度的影响。实际上,对于TSPO和淀粉样蛋白,下丘脑比背侧海马更早受到影响,腹侧海马更晚。在3xtgad小鼠的下丘脑和背侧海马中,观察到TSPO与淀粉样蛋白沉积水平呈正相关。该数据支持以下假设: TSPO可以用作淀粉样蛋白病理的预测标记。此外,我们的免疫组织化学数据显示海马中TSPO的分离,免疫荧光成像显示TSPO表达的主要是小胶质细胞起源。因此,用CLINDE对TSPO进行成像可能是PET放射性示踪剂的良好替代品。
  • 【3xTgAD小鼠的海马和大脑皮层中淀粉样 β 肽损害了质膜氧化还原系统。】 复制标题 收藏 收藏
    DOI:10.1016/j.expneurol.2010.07.020 复制DOI
    作者列表:Hyun DH,Mughal MR,Yang H,Lee JH,Ko EJ,Hunt ND,de Cabo R,Mattson MP
    BACKGROUND & AIMS: :Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q(10) and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders.
    背景与目标: : 与膜相关的氧化应激与阿尔茨海默氏病 (AD) 中发生的突触功能障碍和神经元变性有关,但其潜在机制尚不清楚。质膜氧化还原系统 (PMRS) 的酶为能量代谢和抗氧化剂的回收提供电子。在这里,我们显示了3xTgAD小鼠 (AD的动物模型) 的海马和大脑皮质质膜中几种PMRS酶的活性选择性降低。我们的结果表明PMRS酶活性降低与辅酶q (10) 水平降低和氧化应激标记物水平升高有关。过表达PMRS酶 (NQO1或细胞色素b5还原酶) 的神经元对淀粉样 β 肽 (a β) 的抵抗力增强。A β 是否以及在何种程度上是3xtgad小鼠中PMRS酶受损的原因尚不清楚。因为这些小鼠也表达突变的tau和presenilin-1,所以一个或多个pmr可能受到这些突变的不利影响。尽管如此,我们的细胞培养研究结果清楚地表明,神经元暴露于Aβ1-42足以损害PMRS酶。AD动物模型中PMRS的损害以及PMRS酶活性保护神经元免受a β 毒性的能力,表明增强PMRS功能是保护神经元免受AD和相关疾病氧化损伤的一种新方法。
  • 【慢性气道过敏在野生型小鼠而不是3xtgad小鼠的大脑中诱导促炎反应。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuroscience.2020.09.005 复制DOI
    作者列表:Sarlus H,Codita A,Wang X,Cedazo-Minguez A,Schultzberg M,Oprica M
    BACKGROUND & AIMS:
    背景与目标:
  • 【钙蛋白酶抑制剂A-705253减轻老年3xtgad小鼠的阿尔茨海默氏病样病理和认知功能下降。】 复制标题 收藏 收藏
    DOI:10.1016/j.ajpath.2012.04.020 复制DOI
    作者列表:Medeiros R,Kitazawa M,Chabrier MA,Cheng D,Baglietto-Vargas D,Kling A,Moeller A,Green KN,LaFerla FM
    BACKGROUND & AIMS:
    背景与目标:
  • 【治疗阿尔茨海默氏病的新型酮体疗法: 饮食酮酯对3xTgAD小鼠阿尔茨海默氏病模型中海马糖酵解和三羧酸循环中间体和氨基酸的影响的社论重点。】 复制标题 收藏 收藏
    DOI:10.1111/jnc.13979 复制DOI
    作者列表:Puchowicz MA,Seyfried TN
    BACKGROUND & AIMS:
    背景与目标:
  • 【3xtgad小鼠在慢性轻度社会压力后表现出行为改变和a β 升高。】 复制标题 收藏 收藏
    DOI:10.1016/j.neurobiolaging.2011.07.005 复制DOI
    作者列表:Rothman SM,Herdener N,Camandola S,Texel SJ,Mughal MR,Cong WN,Martin B,Mattson MP
    BACKGROUND & AIMS:
    背景与目标:
  • 【3xtgad小鼠的性类固醇水平和AD样病理。】 复制标题 收藏 收藏
    DOI:10.1111/j.1365-2826.2012.02374.x 复制DOI
    作者列表:Overk CR,Perez SE,Ma C,Taves MD,Soma KK,Mufson EJ
    BACKGROUND & AIMS: :Decreases in testosterone and 17β-oestradiol (E(2)) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in β-amyloid and tau pathological lesions. Although recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD-like pathology, almost none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age-related changes in testosterone and E(2) concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and nontransgenic (ntg) mice. We report for the first time that circulating and brain testosterone levels significantly increase in male 3xTgAD mice with age, but without changes in AR-immunoreactive (IR) cell number in the hippocampal CA1 or medial amygdala. The age-related increase in hippocampal testosterone levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over-expression of human tau up-regulate the hypothalamic-pituitary-gonadal axis in these mice. Although circulating and brain E(2) levels remained stable with age in both male and female 3xTgAD and ntg mice, ER-IR cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Furthermore, E(2) levels were significantly higher in the hippocampus than in serum, suggesting local production of E(2). Although triple transgenic mice mimic AD-like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions.
    背景与目标: : 睾丸激素和17β-雌二醇 (E(2)) 的减少与阿尔茨海默氏病 (AD) 的风险增加有关,这归因于 β-淀粉样蛋白和tau病理病变的增加。尽管最近的研究已经使用转基因动物模型来测试性类固醇操作对AD样病理的影响,但几乎没有人系统地表征任何突变模型中AD病变与血液或大脑中性类固醇水平之间的关联。本研究评估了在完整的雄性和雌性3xTgAD和非转基因 (ntg) 小鼠中显示AD病理的大脑区域中,睾丸激素和E(2) 浓度以及雄激素受体 (AR) 和雌激素受体 (ER) α 和 β 表达的年龄相关变化。我们首次报道,随着年龄的增长,雄性3xtgad小鼠的循环和脑睾丸激素水平显着增加,但海马CA1或内侧杏仁核中AR免疫反应性 (IR) 细胞数量没有变化。与年龄相关的海马睾丸激素水平的增加与构象tau亚型alz50的增加呈正相关。这些数据表明,人tau的过表达上调了这些小鼠的下丘脑-垂体-性腺轴。尽管雄性和雌性3xtgad和ntg小鼠的循环和脑E(2) 水平随年龄而保持稳定,但雌性转基因小鼠的海马和内侧杏仁核中的ER-IR细胞数量随年龄而降低。此外,海马中的E(2) 水平显着高于血清,表明E(2) 的局部产生。尽管三重转基因小鼠模仿AD样病理,但它们不能完全复制人类性别类固醇水平的变化,并且可能不是研究性别类固醇对AD病变影响的最佳模型。
  • 【3xTgAD老年阿尔茨海默氏病小鼠暴露于环境超细颗粒物后的选择性记忆和行为改变。】 复制标题 收藏 收藏
    DOI:10.1186/s12989-019-0323-3 复制DOI
    作者列表:Jew K,Herr D,Wong C,Kennell A,Morris-Schaffer K,Oberdörster G,O'Banion MK,Cory-Slechta DA,Elder A
    BACKGROUND & AIMS: BACKGROUND:A growing body of epidemiological literature indicates that particulate matter (PM) air pollution exposure is associated with elevated Alzheimer's disease (AD) risk and may exacerbate AD-related cognitive decline. Of concern is exposure to the ultrafine PM (UFP) fraction (≤100 nm), which deposits efficiently throughout the respiratory tract, has higher rates of translocation to secondary organs, like brain, and may induce inflammatory changes. We, therefore, hypothesize that exposure to UFPs will exacerbate cognitive deficits in a mouse model of AD. The present study assessed alterations in learning and memory behaviors in aged (12.5 months) male 3xTgAD and non-transgenic mice following a 2-week exposure (4-h/day, 4 days/week) to concentrated ambient UFPs using the Harvard ultrafine concentrated ambient particle system (HUCAPS) or filtered air. Beginning one month following exposure, locomotor activity, spatial learning and memory, short-term recognition memory, appetitive motivation, and olfactory discrimination were assessed. RESULTS:No effects on locomotor activity were found following HUCAPS exposure (number concentration, 1 × 104-4.7 × 105 particles/cm3; mass concentration, 29-132 μg/m3). HUCAPS-exposed mice, independent of AD background, showed a significantly decreased spatial learning, mediated through reference memory deficits, as well as short-term memory deficits in novel object recognition testing. AD mice displayed diminished spatial working memory, potentially a result of olfactory deficits, and short-term memory. AD background modulated HUCAPS-induced changes on appetitive motivation and olfactory discrimination, specifically enhancing olfactory discrimination in NTg mice. Modeling variation in appetitive motivation as a covariate in spatial learning and memory, however, did not support the conclusion that differences in motivation significantly underlie changes in spatial learning and memory. CONCLUSIONS:A short-term inhalation exposure of aged mice to ambient UFPs at human-relevant concentrations resulted in protracted (testing spanning 1-6.5 months post-exposure) adverse effects on multiple memory domains (reference and short-term memory) independent of AD background. Impairments in learning and memory were present when accounting for potential covariates like motivational changes and locomotor activity. These results highlight the need for further research into the potential mechanisms underlying the cognitive effects of UFP exposure in adulthood.
    背景与目标:
  • 【帕罗西汀的预防性治疗可改善3xtgad小鼠的行为缺陷并延缓淀粉样蛋白和tau病变的发展。】 复制标题 收藏 收藏
    DOI:10.1016/j.expneurol.2007.01.037 复制DOI
    作者列表:Nelson RL,Guo Z,Halagappa VM,Pearson M,Gray AJ,Matsuoka Y,Brown M,Martin B,Iyun T,Maudsley S,Clark RF,Mattson MP
    BACKGROUND & AIMS: :A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.
    背景与目标: : 抑郁症病史是阿尔茨海默氏病 (AD) 的危险因素,表明预防性服用抗抑郁药可能会延缓疾病进程并保留认知功能。在这里,我们报告了抗抑郁药帕罗西汀的对症前治疗可以减轻疾病过程并改善AD的3xtgad小鼠模型的认知能力。每天给五个月大的雄性和雌性3xtgad和非转基因小鼠服用帕罗西汀或生理盐水,持续5个月。在7个月大的小鼠中测试了野外活动,并在10个月时评估了被动回避和莫里斯游泳任务的表现。与非转基因对照小鼠相比,3xtgad小鼠的探索活性降低,被动回避测试中的转移潜伏期增加,Morris空间导航任务的性能受损。帕罗西汀治疗改善了3xTgAD雄性和雌性小鼠的空间导航缺陷,而不影响游泳速度或行进距离,表明可以保留认知功能。与生理盐水处理的3xTgAD小鼠相比,雄性和雌性帕罗西汀处理的3xTgAD小鼠的海马中淀粉样 β 肽 (Abeta) 的水平和Abeta免疫反应性神经元的数量显着降低。与雄性3xtgad小鼠相比,雌性3xtgad小鼠在海马和杏仁核中的tau病理明显减少,帕罗西汀减轻了雄性3xtgad小鼠的tau病理。在小鼠模型中,安全有效的抗抑郁药抑制神经病理变化并改善认知能力的能力表明,预防性施用的此类药物可能会阻止人类AD的发展。
  • 【西酞普兰改善雌性3xtgad小鼠的空间记忆和突触可塑性障碍。】 复制标题 收藏 收藏
    DOI:10.1155/2017/1238687 复制DOI
    作者列表:Wei Z,Junhong G,Xiaoyuan N,Jie W,Zhaojun W,Meina W,Wei Y,Jun Z,Jinshun Q
    BACKGROUND & AIMS: :Alzheimer's disease (AD) is the primary cause of dementia. There is no effective treatment. Amyloid-β peptide (Aβ) plays an important role in the pathogenesis and thus strategies suppressing Aβ production and accumulation seem promising. Citalopram is an antidepressant drug and can decrease Aβ production and amyloid plaques in transgenic mice of AD and humans. Whether citalopram can ameliorate memory deficit was not known yet. We tested the effects of citalopram on behavioral performance and synaptic plasticity in female 3xTgAD mice, a well-characterized model of AD. Mice were treated with citalopram or water from 5 months of age for 3 months. Citalopram treatment at approximately 10 mg/kg/day significantly improved spatial memory in the Morris water maze (MWM) test, while not affecting anxiety-like and depression-like behavior in 3xTgAD mice. Further, hippocampal long-term potentiation (LTP) impairment in 3xTgAD mice was reversed by citalopram treatment. Citalopram treatment also significantly decreased the levels of insoluble Aβ40 in hippocampal and cortical tissues in 3xTgAD mice, accompanied with a reduced amyloid precursor protein (APP). Together, citalopram treatment may be a promising strategy for AD and further clinical trials should be conducted to verify the effect of citalopram on cognition in patients with AD or mild cognitive impairment.
    背景与目标: : 阿尔茨海默氏病 (AD) 是痴呆症的主要原因。没有有效的治疗方法。淀粉样 β 肽 (a β) 在发病机理中起着重要作用,因此抑制a β 产生和积累的策略似乎很有希望。西酞普兰是一种抗抑郁药,可以减少AD和人类转基因小鼠中a β 的产生和淀粉样斑块。西酞普兰是否能改善记忆缺陷尚不清楚。我们测试了西酞普兰对雌性3xtgad小鼠 (一种特征良好的AD模型) 的行为表现和突触可塑性的影响。从5个月大的小鼠用西酞普兰或水治疗3个月。在Morris水迷宫 (MWM) 测试中,约10 mg/kg/天的西酞普兰治疗可显着改善空间记忆,而不影响3xtgad小鼠的焦虑样和抑郁样行为。此外,西酞普兰治疗可逆转3xtgad小鼠的海马长时程增强 (LTP) 损伤。西酞普兰治疗还显着降低了3xtgad小鼠海马和皮质组织中不溶性Aβ40的水平,并伴有淀粉样蛋白前体蛋白 (APP) 降低。总之,西酞普兰治疗可能是AD的一种有前途的策略,应进行进一步的临床试验以验证西酞普兰对AD或轻度认知障碍患者认知功能的影响。
  • 【Presenilin-1突变会损害突触可塑性的胆碱能调节并抑制海马切片中的NMDA电流。】 复制标题 收藏 收藏
    DOI:10.1016/j.neurobiolaging.2007.10.009 复制DOI
    作者列表:Wang Y,Greig NH,Yu QS,Mattson MP
    BACKGROUND & AIMS: :Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid beta-peptide (Abeta). However, Abeta-independent effects of mutant PS1 on neuronal Ca(2+) homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca(2+)chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.
    背景与目标: : Presenilin-1 (PS1) 突变导致许多早发性遗传性阿尔茨海默氏病的病例,部分原因是增加了神经毒性形式的淀粉样 β 肽 (Abeta) 的产生。然而,已经报道了突变体PS1对神经元Ca(2) 稳态和对兴奋性神经递质敏感性的 β 非依赖性作用。在这里,我们显示了PS1突变体敲除蛋白 (PS1KI) 小鼠海马突触可塑性的胆碱能调节受损。毒蕈碱受体的激活增强了正常小鼠CA1突触处的LTP,但损害了PS1KI小鼠的LTP。同样,突变体PS1会损害胆碱酯酶抑制剂phenserine增强LTP的能力。在PS1KI小鼠的CA1神经元中NMDA电流降低,并通过细胞内Ca(2) 螯合恢复。在具有PS1,淀粉样蛋白前体蛋白和tau突变的3xtgad小鼠中,乙酰胆碱和NMDA受体介导的突触可塑性成分的类似改变也很明显,这表明在不存在或存在淀粉样蛋白的情况下,突变体PS1对突触可塑性的不利影响可能发生和tau病理。

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