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

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

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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），并代谢支持神经元活性。在阿尔茨海默氏病（AD）中，星形胶质细胞在淀粉样蛋白附近变成反应性（a斑块，有助于进行神经炎症，并参与突触和电路异常。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，但仍然未知。关系在星形胶质细胞和BBB之间特别有趣，因为血管功能障碍是危险因素在星形胶质细胞和BBB之间发展AD和相互作用会导致协同功能障碍在疾病进展中。此外，破坏星形胶质细胞和BBB功能的创伤性脑损伤是一种风险 AD和相关痴呆症的因素。兴奋性氨基酸转运蛋白（EAATS：GLT-1和GLAST）和内部纠正K+通道，包括Kir4.1，为星形胶质细胞提供了两个基本功能，从而占用细胞外谷氨酸和K+。父母R21中的初步啮齿动物数据识别新型星形胶质细胞正常衰老期间的表型，其中逐渐更多的星形胶质细胞失去EAAT和KIR4.1表达。这与年龄相关的损失不是等级，全球变化，而是单个星形胶质细胞的细胞基础发生表达最小的EAAT和KIR4.1，而相邻的星形胶质细胞保持正常。这些的外观 “非典型星形胶质细胞”（ATA）发生在脉管系统附近和BBB妥协区域附近。在这个补充要求，我们建议将ATA的研究扩展到阿尔茨海默氏症的小鼠模型疾病（AD）。 ATA代表一种新的星形胶质细胞，可能对大脑具有重要意义功能和神经疾病。此前曾在轻度创伤性脑损伤（MTBI）之前报道过ATA 并被认为与BBB的损伤妥协有关。在父母R21中，我们报告了在皮质的特定区域的衰老大脑中也发现了ATA，并且BBB功能障碍和异常在发现ATA的区域中可以看到星形胶质细胞谷氨酸摄取，显示出ATA的功能后果。在此补充要求中，我们将利用阿尔茨海默氏病的AppNL-G-F小鼠模型（AD），该模型在APP蛋白中包含3种引起人病的突变。我们包括ATA的初步数据与WTS相比，AppNL-G-F小鼠的海马富含。我们假设ATA是更多由于BBB功能障碍，在AppNL-G-F小鼠中常见，与星形胶质细胞蛋白的丧失有关 Aquaporin-4（AQP-4）。 AQP-4对于从大脑中去除A很重要，因此存在更多的ATA，而ATA的存在缺乏AQP-4，可能导致A斑块形成增加。此外，我们建议检查 appnl-g-f小鼠中的mtbi。因为我们怀疑AppNL-G-F小鼠容易发生BBB功能障碍，所以我们假设 MTBI将导致BBB妥协增加并导致更多ATA。如果正确，这些研究将暗示 ATA可能在AD的病理中发挥作用，将通过ATA将BBB妥协与A斑块形成联系起来，并将支持靶向星形胶质细胞AQP-4功能以减少与广告相关的病理。