Atypical astrocytes in the aging cortex

老化皮质中的非典型星形胶质细胞

基本信息

  • 批准号:
    10711455
  • 负责人:
  • 金额:
    $ 20.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Astrocytes control neurotransmission, contribute to the blood-brain-barrier (BBB), and metabolically support neuronal activity. In Alzheimer’s Disease (AD), astrocytes become reactive near amyloid (A plaques, contribute to neuroinflammation, and are involved in synaptic and circuit abnormalities. Growing evidence also suggests astrocyte dysfunction may play a role in early disease progression, but much remains unknown. The relationship between astrocytes and the BBB is particularly intriguing in AD because vascular dysfunction is a risk factor for developing AD and reciprocal interactions between astrocytes and the BBB can lead to synergistic dysfunction in disease progression. In addition, traumatic brain injury, which disrupts astrocyte and BBB function, is a risk factor for AD and related dementias. Excitatory amino acid transporters (EAATs: GLT-1 and GLAST) and inwardly rectifying K+ channels, including Kir4.1, give astrocytes two of their fundamental functions, taking up extracellular glutamate and K+, respectively. Preliminary rodent data in the parent R21 identifies a novel astrocyte phenotype during normal aging in which progressively more astrocytes lose EAAT and Kir4.1 expression. This age-related loss is not a gradual, global change but rather occurs on a cell-by-cell basis with individual astrocytes expressing minimal EAAT and Kir4.1, while neighboring astrocytes remain normal. The appearance of these “atypical astrocytes” (AtAs) occurs near vasculature and in areas of BBB compromise. In this supplement request, we propose to extend our studies of AtAs into a mouse model of Alzheimer’s Disease (AD). AtAs represents a new subtype of astrocytes that could have important implications for brain function and neurological disease. AtA have been previously reported follow mild traumatic brain injury (mTBI) and are thought to be associated with injury-related compromise of the BBB. In the parent R21, we reported that AtAs are also found in the aging brain in specific regions of the cortex and that BBB dysfunction and abnormal astrocyte glutamate uptake is seen in regions where AtAs are found, showing a functional consequence of AtAs. In this supplement request, we will utilize the APPNL-G-F mouse model of Alzheimer’s Disease (AD), which contains 3 human disease-causing mutations in the APP protein. We include preliminary data that AtAs are more abundant in the hippocampus of APPNL-G-F mice, as compared to WTs. We hypothesize that AtAs are more common in APPNL-G-F mice due to BBB dysfunction and are associated with the loss of the astrocyte protein aquaporin-4 (AQP-4). AQP-4 is important in removing A from the brain, so the presence of more AtAs, which lack AQP-4, could lead to increases in A plaque formation. In addition, we propose to examine the effects of mTBI in APPNL-G-F mice. Because we suspect that APPNL-G-F mice are prone to BBB dysfunction, we hypothesize that mTBI will induce increased BBB compromise and lead to more AtAs. If correct, these studies will suggest AtAs may play a role in the pathology of AD, will link BBB compromise to A plaque formation via AtA, and would support targeting astrocyte AQP-4 function to reduce AD-related pathology.
摘要 星形胶质细胞控制神经传递,有助于血脑屏障(BBB),并在代谢上提供支持 神经元活动。在阿尔茨海默病(AD)中,星形胶质细胞在淀粉样蛋白附近变得活跃(A斑块,有助于 神经炎症,并参与突触和回路的异常。越来越多的证据也表明 星形胶质细胞功能障碍可能在早期疾病进展中发挥作用,但仍有许多未知之处。两国关系 星形胶质细胞和血脑屏障之间的关系在AD中特别耐人寻味,因为血管功能障碍是 发展为阿尔茨海默病以及星形胶质细胞和血脑屏障之间的相互作用可导致协同功能障碍 在疾病的发展过程中。此外,破坏星形胶质细胞和血脑屏障功能的创伤性脑损伤也是一种风险。 阿尔茨海默病和相关痴呆的因素。兴奋性氨基酸转运体(EAATs:GLT-1和GLAST)和 向内整流K+通道,包括Kir4.1,赋予星形胶质细胞两项基本功能,包括 胞外谷氨酸和K+。亲本R21中的初步啮齿动物数据鉴定出一种新的星形胶质细胞 在正常老化过程中,逐渐有更多的星形胶质细胞失去EAAT和Kir4.1的表达。这 与年龄相关的丢失不是渐进的、全球性的变化,而是逐个细胞地发生在单个星形胶质细胞的基础上 表达最小的EAAT和Kir4.1,而邻近的星形胶质细胞保持正常。这些东西的出现 “非典型星形细胞”(ATA)发生在血管附近和血脑屏障受损区域。在这 补充要求,我们建议将我们对atas的研究扩展到阿尔茨海默病的小鼠模型。 疾病(AD)。ATAS代表了一种新的星形胶质细胞亚型,可能对大脑有重要意义 功能和神经疾病。ATA此前已被报道与轻度创伤性脑损伤(MTBI)有关。 并被认为与受伤相关的BBB损害有关。在父代R21中,我们报告了 在老化的大脑皮质的特定区域也发现了ATA,BBB功能障碍和异常 星形胶质细胞谷氨酸摄取见于发现ATAS的区域,显示ATAS的功能后果。 在本补充申请中,我们将利用APPNL-G-F阿尔茨海默病(AD)小鼠模型,该模型 在APP蛋白中包含3个导致人类疾病的突变。我们包括了初步数据,即ATA更多 与WTS相比,APPNL-G-F小鼠海马区含量丰富。我们假设ATA比 APPNL-G-F小鼠由于血脑屏障功能障碍而常见,并与星形胶质细胞蛋白的丢失有关 水通道蛋白4(AQP-4)。AQP-4在从大脑中移除A方面很重要,因此更多ATA的存在,即 缺乏水通道蛋白-4,可能导致A斑块形成增加。此外,我们建议研究以下因素的影响: APPNL-G-F小鼠MTBI。因为我们怀疑APPNL-G-F小鼠容易出现血脑屏障功能障碍,所以我们假设 MTBI会导致血脑屏障损害增加,并导致更多的ATA。如果是正确的,这些研究将表明 ATAS可能在AD的病理过程中发挥作用,通过ATA将血脑屏障损害与A斑块形成联系起来,并将 支持靶向星形胶质细胞AQP-4功能,减少AD相关病理改变。

项目成果

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Chris G Dulla其他文献

Who let the spikes out?
谁把尖刺放出来了?
  • DOI:
    10.1038/nn0809-959
  • 发表时间:
    2009-08-01
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Chris G Dulla;John R Huguenard
  • 通讯作者:
    John R Huguenard

Chris G Dulla的其他文献

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{{ truncateString('Chris G Dulla', 18)}}的其他基金

Using Single Cell Biological Approaches to Understand CNS TB
使用单细胞生物学方法了解中枢神经系统结核
  • 批准号:
    10739081
  • 财政年份:
    2023
  • 资助金额:
    $ 20.62万
  • 项目类别:
Voltage Imaging of Astrocyte-Neuron Interactions
星形胶质细胞-神经元相互作用的电压成像
  • 批准号:
    10711423
  • 财政年份:
    2023
  • 资助金额:
    $ 20.62万
  • 项目类别:
Atypical astrocytes in the aging cortex
老化皮质中的非典型星形胶质细胞
  • 批准号:
    10552699
  • 财政年份:
    2022
  • 资助金额:
    $ 20.62万
  • 项目类别:
Atypical astrocytes in the aging cortex
老化皮质中的非典型星形胶质细胞
  • 批准号:
    10382048
  • 财政年份:
    2022
  • 资助金额:
    $ 20.62万
  • 项目类别:
Utilizing Single Cell Biological Approaches to Understand CNS TB
利用单细胞生物学方法了解中枢神经系统结核
  • 批准号:
    10023220
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:
Voltage imaging of astrocyte-neuron interactions
星形胶质细胞-神经元相互作用的电压成像
  • 批准号:
    9913654
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:
Voltage imaging of astrocyte-neuron interactions
星形胶质细胞-神经元相互作用的电压成像
  • 批准号:
    10433036
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:
Voltage imaging of astrocyte-neuron interactions
星形胶质细胞-神经元相互作用的电压成像
  • 批准号:
    10433847
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:
Voltage imaging of astrocyte-neuron interactions
星形胶质细胞-神经元相互作用的电压成像
  • 批准号:
    10192852
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:
Utilizing Single Cell Biological Approaches to Understand CNS TB
利用单细胞生物学方法了解中枢神经系统结核
  • 批准号:
    9817044
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:

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