BACKGROUND & AIMS: :Alzheimer disease is the most common neurodegenerative disorder and cause of senile dementia. It is characterized by an accelerated memory loss, and alterations of mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are β-amyloid (βA) plaques and neurofibrillary Tau tangles. The triple transgenic 3xTgAD mouse model develops βA and Tau pathologies in a progressive manner which mimicks the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. The present study intended to examine whether 3xTgAD mice of both sexes present cognitive, emotional and other behavioral alterations at the early age of 4 months, an age in which only some intraneuronal amyloid accumulation is found. Neonatal handling (H) is an early-life treatment known to produce profound and long-lasting behavioral and neurobiological effects in rodents, as well as improvements in cognitive functions. Therefore, we also aimed at evaluating the effects of H on the behavioral/cognitive profile of 4-month-old male and female 3xTgAD mice. The results indicate that, (1) 3xTgAD mice present spatial learning/memory deficits and emotional alterations already at the early age of 4 months, (2) there exists sexual dimorphism effects on several behavioral variables at this age, (3) neonatal handling exerts a preventive effect on some cognitive (spatial learning) and emotional alterations appearing in 3xTgAD mice already at early ages, and 4) H treatment appears to produce stronger positive effects in females than in males in several spatial learning measures and in the open field test.

背景与目标： : 阿尔茨海默病是最常见的神经退行性疾病和老年性痴呆的原因。它的特征是加速记忆丧失，以及情绪，理性，判断力和语言的改变。该疾病的主要神经病理学特征是 β-淀粉样蛋白 (β a) 斑块和神经原纤维Tau缠结。三重转基因3xtgad小鼠模型以渐进的方式发展 β a和Tau病理，模仿了AD在人脑中发生的模式，并显示出该疾病的认知特征。本研究旨在检查3个xTgAD小鼠在4个月大时是否表现出认知，情感和其他行为上的改变，该年龄仅发现一些神经内淀粉样蛋白积聚。新生儿处理 (H) 是一种早期治疗方法，已知会在啮齿动物中产生深刻而持久的行为和神经生物学作用，并改善认知功能。因此，我们还旨在评估H对4个月大的雄性和雌性3xtgad小鼠的行为/认知特征的影响。结果表明 :( 1) 3个xTgAD小鼠在4个月的早期就已经存在空间学习/记忆缺陷和情绪改变，(2) 在该年龄对几个行为变量存在性二态性影响，(3) 新生儿处理对早期3xTgAD小鼠中出现的某些认知 (空间学习) 和情绪改变具有预防作用，并且4) H处理似乎在几种空间学习措施中，女性比男性产生更强的积极作用。和在野外测试中。

BACKGROUND & AIMS: :Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

背景与目标： : 阿尔茨海默氏病 (AD) 的特征不仅是认知缺陷和神经病理变化，而且还包括一些可能导致生活质量下降的非认知行为症状。据报道，AD患者的核心体温和身体活动的昼夜节律紊乱，尽管这些变化的原因和后果尚不清楚。因此，我们通过远程无线电遥测表征了雄性三重转基因AD小鼠 (3xTgAD) 和非转基因 (non-Tg) 对照小鼠的体温和活动的昼夜节律模式。在4个月大时，每天的温度节律是阶段性的，到6个月大时，在3xtgad小鼠中观察到平均核心体温和温度节律幅度的增加。在4至9个月大的3xtgad小鼠中，日常活动节律没有差异，但是到10个月大时，检测到3xtgad小鼠的平均日常活动增加和活动曲线的幅度。在所有年龄 (4-10个月)，与非Tg小鼠相比，3xtgad小鼠的食物摄入量更高。温度的变化似乎并不仅仅是由于食物摄入量的增加，并且不是环氧合酶依赖性的，因为慢性布洛芬治疗并未消除温度升高。在3xtgad小鼠的下丘脑中未发现 β-淀粉样蛋白 (a β) 斑块或神经原纤维缠结，这是温度调节的关键区域，尽管在10个月大的3xtgad小鼠的海马和杏仁核中观察到这些病理特征。这些数据证明了3xTgAD小鼠的核心体温和活动的年龄依赖性变化，这些变化在明显的AD相关神经病理学之前存在，与在AD患者中观察到的相似。因此，3xtgad小鼠可能是研究AD非认知行为变化所涉及的潜在机制的合适模型。

BACKGROUND & AIMS: :Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca(2+) currents (L-VGCC), 4-aminopyridine-sensitive K(+) currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid β-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca(2+) channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K(+) or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca(2+), K(+), AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients.

背景与目标： : 阿尔茨海默病 (AD) 的神经元变性和死亡之前，可能会发生异常的神经元兴奋性和突触可塑性受损。为了阐明AD中异常神经元网络活动潜在的生物物理变化，我们对L型 (硝苯地平敏感) Ca(2) 电流 (l-vgcc)，4-氨基吡啶敏感的K () 电流进行了全细胞膜片钳分析，和AMPA (2-氨基-3-(3-羟基-5-甲基-异恶唑-4-基) 丙酸) 和NMDA (N-甲基-D-天冬氨酸) 电流在海马的CA1，CA3和牙齿颗粒神经元中来自年轻，中年，3xTgAD小鼠和年龄匹配的野生型小鼠。3xTgAD小鼠在海马CA1神经元中发展出淀粉样 β 肽的进行性广泛积累和选择性过度磷酸化的tau病理，这与认知缺陷有关。但与明显的神经元变性无关。3xTgAD小鼠CA1神经元的L型Ca(2) 通道电流密度与年龄有关，但野生型小鼠则没有。在老年3xtgad小鼠中，其幅度明显更大。与老年野生型小鼠相比，老年3xtgad小鼠的CA1神经元中NMDA电流也显着升高。与野生型小鼠相比，3xtgad小鼠的CA1神经元中K () 或AMPA电流的幅度没有差异型小鼠在任何年龄。Ca(2 +)，与任何年龄的野生型小鼠相比，来自3xtgad小鼠的CA3和齿状神经元中的K(+)，AMPA或NMDA电流。我们的结果揭示了CA1神经元中L-VGCC密度的年龄相关增加，但CA3或齿状颗粒神经元中则没有，3xTgAD小鼠。这些发现表明，L-VGCC改变对3xTgAD小鼠中CA1神经元对tau病理的选择性脆弱性及其在AD患者中的变性的潜在贡献。

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：

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。

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。

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。

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。

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。

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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。

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.

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