• 【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。
  • 【在阿尔茨海默氏病的小鼠模型中,DNA聚合酶 β 的减少会触发嗅球细胞的死亡并损害嗅觉。】 复制标题 收藏 收藏
    DOI:10.1111/acel.12541 复制DOI
    作者列表:Misiak M,Vergara Greeno R,Baptiste BA,Sykora P,Liu D,Cordonnier S,Fang EF,Croteau DL,Mattson MP,Bohr VA
    BACKGROUND & AIMS: :Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase-β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild-type and 3xTgAD mice with normal or reduced Polβ levels. Compared to wild-type control mice, Polβ heterozygous (Polβ+/- ), and 3xTgAD mice, 3xTgAD/Polβ+/- mice exhibited impaired performance in a buried food test of olfaction. Polβ deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Polβ+/- and 3xTgAD mice, and by over 60% in the 3xTgAD/Polβ+/- mice compared to wild-type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Polβ+/- mice compared to 3xTgAD mice. Levels of amyloid β-peptide (Aβ) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Polβ+/- mice, and cultured Polβ-deficient neurons exhibited increased vulnerability to Aβ-induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.
    背景与目标: : 阿尔茨海默氏病 (AD) 涉及对学习和记忆至关重要的神经元的进行性退化。此外,AD患者通常表现出与嗅球 (OB) 神经元变性相关的嗅觉受损。由于在正常衰老和AD期间脑细胞中的DNA碱基切除修复 (BER) 减少,因此我们确定了由于DNA聚合酶-β (pol β) 水平降低而导致的低效BER是否使OB神经元容易在3xtgad小鼠模型中变性AD。我们询问了pol β 水平正常或降低的野生型和3xtgad小鼠的OB组织病理学和嗅觉功能。与野生型对照小鼠,pol β 杂合 (pol β/-) 和3xTgAD小鼠相比,3xTgAD/pol β/-小鼠在掩埋的嗅觉食物测试中表现出受损的表现。Pol β 缺乏不影响脑室下区OB神经祖细胞的增殖。然而,与野生型对照小鼠相比,在pol β +/-和3xtgad小鼠中,新生神经元的数量减少了约25%,在3xtgad/pol β +/-小鼠中减少了60% 以上。对DNA损伤和凋亡的分析显示,与3xtgad小鼠相比,3xtgad/pol β/-小鼠的OB神经元变性明显更大。在3xtgad和3xtgad/pol β/-小鼠中,OB中淀粉样 β 肽 (a β) 积累的水平相似,并且培养的pol β 缺陷神经元对a β 诱导的死亡表现出更高的脆弱性。嗅觉不足是人类AD的早期迹象,但其机制尚不清楚。我们在新的AD小鼠模型中的发现表明,BER的减少会危及OB神经元,并暗示了AD早期嗅觉受损的潜在机制。
  • 【毒蕈碱M1受体的丧失会加剧阿尔茨海默氏病样病理和认知能力下降。】 复制标题 收藏 收藏
    DOI:10.1016/j.ajpath.2011.04.041 复制DOI
    作者列表:Medeiros R,Kitazawa M,Caccamo A,Baglietto-Vargas D,Estrada-Hernandez T,Cribbs DH,Fisher A,LaFerla FM
    BACKGROUND & AIMS: :Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and β-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M(1) receptors (M(1)Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M(1)Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M(1)R(-/-) mice. Our data show that M(1)R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M(1)R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Aβ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M(1)R were attributed to changes in the glycogen synthase kinase 3β and protein kinase C activities. Finally, deleting the M(1)R increased the astrocytic and microglial response associated with Aβ plaques. Our data highlight the significant role that disrupting the M(1)R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M(1)R agonists for treating AD.
    背景与目标: : 阿尔茨海默氏病 (AD) 的病理特征是富含tau的神经原纤维缠结和 β-淀粉样蛋白沉积。胆碱能神经传递的失调与AD发病机理有关,导致相关的记忆障碍; 然而,确切的机制仍有待确定。激活毒蕈碱型乙酰胆碱M(1) 受体 (M(1)Rs) 可减少AD样病理特征并增强AD转基因模型的认知。为了阐明M(1)Rs影响AD病理生理特征的分子机制,我们杂交了3xTgAD和表达人类瑞典,荷兰和爱荷华州三重突变淀粉样蛋白前体蛋白 (tg-swdi) 的转基因小鼠,这两种广泛使用的动物模型,与M(1)R(-/-) 小鼠。我们的数据表明,3xTgAD和Tg-SwDI小鼠中的M(1)R缺失通过依赖于记忆所需基因的转录失调的机制以及通过加速AD相关的突触毒性而加剧了认知障碍。消融M(1)R增加了3xtgad小鼠大脑中的斑块和缠结水平,并增加了Tg-SwDI小鼠中原纤维a β 的脑血管沉积。值得注意的是,AD缺乏M(1)R的小鼠的tau过度磷酸化和淀粉样蛋白生成过程的增强归因于糖原合酶激酶3β 和蛋白激酶C活性的变化。最后,删除M(1)R会增加与a β 斑块相关的星形细胞和小胶质细胞反应。我们的数据强调了破坏M(1)R在加剧AD相关的认知衰退和病理特征中的重要作用,并提供了重要的临床前证据,以证明进一步开发和评估选择性M(1)R激动剂治疗AD。
  • 【在衰老的3xtgad和nonTg小鼠中,别孕纳龙可恢复海马依赖性学习和记忆以及神经祖细胞的存活。】 复制标题 收藏 收藏
    DOI:10.1016/j.neurobiolaging.2011.06.008 复制DOI
    作者列表:Singh C,Liu L,Wang JM,Irwin RW,Yao J,Chen S,Henry S,Thompson RF,Brinton RD
    BACKGROUND & AIMS: :We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.
    背景与目标: : 我们先前证明了在阿尔茨海默氏病 (AD) 病理之前,allopregnanolone (ap α) 增加了神经祖细胞的增殖并逆转了神经源性和认知缺陷 (Wang,J.M.,Johnston,P.B.,Ball,b.g.,Brinton,R.D.,2005.神经甾体异戊二醇酮促进啮齿动物和人神经祖细胞的增殖,并调节细胞周期基因和蛋白质的表达。J. Neurosci。25,4706-4718; Wang,j.m.,Singh,C.,Liu,L.,Irwin,R.W.,Chen,S.,Chung,E.J.,Thompson,R.F.,Brinton,R.D.,2010。Allopregnanolone逆转阿尔茨海默氏病小鼠模型中的神经源性和认知缺陷。Proc. Natl. Acad. Sci.美国107,6498-6503)。在本文中,我们确定了ap α 在雄性3xtgad小鼠及其非转基因 (nonTg) 对应物中恢复神经祖细胞存活以及AD病理后的联想学习和记忆的功效。在存在神经内淀粉样蛋白 β (a β) 的情况下,APα 显着增加了3xtgad小鼠的溴脱氧尿苷阳性 (BrdU) 细胞和海马依赖性联想学习和记忆,而APα 在神经外a β 斑块形成后无效。海马依赖性联想学习的恢复在第一天达到最大,并在整个行为训练中持续。在APα 处理的3xtgad小鼠中,学习和记忆功能100% 大于赋形剂处理的小鼠,并且与最大正常非tg表现相当。在15个月大的nonTg小鼠中,ap α 显着提高了溴脱氧尿苷阳性细胞和海马依赖性联想学习和记忆的存活率。结果提供了临床前证据,表明ap α 促进了新生细胞的存活,并在AD病理的斑块前期和正常衰老后期恢复了认知能力。

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