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：
Chris G Dulla
金额：
$ 20.62万
依托单位：
TUFTS UNIVERSITY BOSTON
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

来源：
https://reporter.nih.gov/project-details/10711455
关键词：
Acceleration Affect Age Age Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amino Acid Transporter Amyloid Anatomy Animals Appearance Area Astrocytes Astrocytosis Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Cells Cerebrovascular Disorders Data Deposition Development Disease Progression Excitatory Amino Acids Extravasation Functional disorder GLAST Protein Glial Fibrillary Acidic Protein Global Change Glutamates Hippocampus Human Individual Injury Lead Link Memory impairment Metabolic Modeling Morphology Mus Neurons Parents Pathology Phenotype Proteins Reporting Risk Factors Rodent Site Synapses System Testing Traumatic Brain Injury Vascular Diseases Work age related aged aging brain aquaporin 4 blood-brain barrier disruption blood-brain barrier function disease-causing mutation early onset excitotoxicity extracellular human disease immunoreactivity inward rectifier potassium channel mild traumatic brain injury mouse model nervous system disorder neuroinflammation neurotransmission normal aging novel overexpression uptake

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.

抽象的星形胶质细胞控制神经传递，有助于血脑屏障 (BBB) 和代谢支持在阿尔茨海默病 (AD) 中，星形胶质细胞在淀粉样蛋白（A 斑块）附近变得活跃。越来越多的证据还表明，它与神经炎症有关，并与突触和回路异常有关。星形胶质细胞功能障碍可能在早期疾病进展中发挥作用，但其中的关系仍不清楚。星形胶质细胞和 BBB 之间的关系在 AD 中特别令人感兴趣，因为血管功能障碍是 AD 的危险因素 AD 的发展以及星形胶质细胞和 BBB 之间的相互作用可导致协同功能障碍此外，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。 AD 和相关痴呆症的因子（EAAT：GLT-1 和 GLAST）和内向整流 K+ 通道（包括 Kir4.1）赋予星形胶质细胞两个基本功能，母体 R21 中的细胞外谷氨酸和 K+ 的初步啮齿动物数据分别鉴定出一种新的星形胶质细胞。正常衰老过程中，越来越多的星形胶质细胞失去 EAAT 和 Kir4.1 表达。与年龄相关的损失不是渐进的、全局的变化，而是在单个星形胶质细胞的逐个细胞的基础上发生表达最少的 EAAT 和 Kir4.1，而邻近的星形胶质细胞的外观保持正常。 “非典型星形胶质细胞”（AtAs）出现在脉管系统附近和血脑屏障受损的区域。根据补充要求，我们建议将 AtAs 的研究扩展到阿尔茨海默氏症小鼠模型 AtAs 疾病（AD）代表了一种新的星形胶质细胞亚型，可能对大脑产生重要影响。此前已有报道称，轻度创伤性脑损伤 (mTBI) 后会出现 AtA 功能和神经系统疾病。并被认为与 BBB 损伤相关的损害有关。在母体 R21 中，我们报道了这一点。 AtAs 也存在于老化大脑皮层特定区域中，并且 BBB 功能障碍和异常在发现 AtAs 的区域中可以看到星形胶质细胞摄取谷氨酸，这表明 AtAs 的功能性结果。在此补充请求中，我们将利用阿尔茨海默病 (AD) 的 APPNL-G-F 小鼠模型，该模型 APP 蛋白中含有 3 种导致人类疾病的突变，我们提供的初步数据表明 AtAs 更多。与 WT 小鼠相比，APPNL-G-F 小鼠的海马中 AtAs 含量更高。由于 BBB 功能障碍，在 APPNL-G-F 小鼠中常见，并且与星形胶质细胞蛋白的丢失有关水通道蛋白-4 (AQP-4) 对于从大脑中去除 A 很重要，因此存在更多的 AtAs，这缺乏 AQP-4，可能会导致 A 斑块形成增加。此外，我们建议检查 A 斑块形成的影响。 APPNL-G-F 小鼠的 mTBI 因为我们怀疑 APPNL-G-F 小鼠容易出现 BBB 功能障碍，所以我们勇敢地进行。如果正确的话，这些研究将表明 mTBI 会导致 BBB 受损增加并导致更多 AtAs。 AtAs 可能在 AD 病理学中发挥作用，通过 AtA 将 BBB 受损与 A 斑块形成联系起来，并且支持靶向星形胶质细胞 AQP-4 功能，以减少 AD 相关病理。