White Matter Injury and Repair in Vascular Cognitive Impairment and Dementia

血管认知障碍和痴呆症中的白质损伤和修复

基本信息

批准号：
10630775
负责人：
Xiaoming Hu
金额：
$ 135.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630775
关键词：
Adipocytes Affect Agonist Alzheimer&apos s Disease Area Axon Blood Blood Vessels Brain Injuries Carotid Stenosis Cell Differentiation process Cells Central Nervous System Diseases Cessation of life Chronic Clinical Clinical Treatment Cognitive deficits Common carotid artery Data Dementia Demyelinations Development Disease Effectiveness Elderly Elderly man Elderly woman Failure Female Fostering Glucose Hippocampus Homeostasis Hypoxia Impaired cognition Impairment In Vitro Inflammation Inflammatory Ischemic Stroke Knockout Mice Lesion Mediator Microglia Modeling Mus Myelin Natural regeneration Nervous System Physiology Neurons Oligodendroglia Outcome Oxygen Pathology Perfusion Phagocytosis Phenotype Play Property Proteins Recovery of Function Reporting Role Testing Therapeutic adipokines adiponectin aged aging brain aging population arteriole cerebral hypoperfusion cognitive function conditional knockout cytokine density deprivation functional improvement hypoperfusion improved in vivo injury and repair male mouse model neuroinflammation neuron loss novel novel therapeutics oligodendrocyte precursor precursor cell receptor repaired response sex small molecule therapeutic target vascular cognitive impairment and dementia white matter white matter damage white matter injury

项目摘要

Vascular cognitive impairment and dementia (VCID) is the second most common type of dementia. No protective or disease-modifying strategies are available to reverse or halt VCID. A major feature of VCID is white matter pathology, including demyelination and a loss of myelin producing cells, which are highly correlated with cognitive deficits in the aged population. Oligodendrocyte precursor cell (OPC) differentiation occurs in white matter enriched areas upon chronic hypoxia but is insufficient for white matter repair. Thus, a legitimate strategy to improve functional outcomes in VCID is to enhance white matter integrity by protecting oligodendrocytes and by promoting oligodendrocyte regeneration. Adiponectin, the most abundant adipokine in the blood, plays a crucial role in CNS pathologies. We have reported that adiponectin is important for cognitive function and reduces hippocampal neuronal loss in the asymmetric common carotid artery stenosis (ACAS) mouse model of VCID. However, the effects of adiponectin on white matter integrity after VCID are unknown. To fill this important gap, we recently evaluated the functional impact of adiponectin on white matter components after ACAS in young mice. Our pilot data show that adiponectin deficiency reduces white matter integrity and impairs axonal conduction 42d after ACAS. Adiponectin knockout (KO) mice display greater oligodendrocyte loss and less oligodendrocyte regeneration. In contrast, treatment with adipoRon, a small-molecule agonist of adiponectin receptors, improves long-term white matter integrity and leads to superior cognitive functions up to 42d after ACAS. We observed that adiponectin receptor 1 (adipoR1) is highly expressed on oligodendrocytes and microglia in vivo. In vitro data further suggest that adipoRon protects cultured oligodendrocytes against oxygen/glucose deprivation through AMPK activation. AdipoRon also enhances microglial phagocytosis and promotes the oligodendrogenic capacities of microglia. Based on these promising data, we will test the new hypothesis that adiponectin promotes structural and functional white matter integrity and improves neurological function in chronic cerebral hypoperfusion- induced VCID by dual mechanisms: 1) enhancing oligodendrocyte survival through AMPK activation, and 2) promoting a reparative microglial phenotype with high oligodendrogenic capacities. Three Specific Aims will be tested. Aim 1: Test if adiponectin protects oligodendrocytes in an AMPK-dependent manner to improve white matter integrity after ACAS. Aim 2: Test if adiponectin shifts microglia toward a reparative phenotype that enhances OPC differentiation after ACAS. Aim 3: Test if adipoRon treatment enhances white matter integrity and improves long-term cognitive functions after ACAS in aged mice of both sexes. These studies will shed light on adiponectin as a key mediator to improve white matter integrity in VCID. Positive outcomes would also hasten the development of adipoRon as a clinical treatment in elderly men and women with VCID.

血管认知障碍和痴呆症（VCID）是第二常见的痴呆类型。没有保护或改善疾病的策略可以逆转或停止VCID。 VCID的主要特征是白色物质病理学，包括脱髓鞘和髓磷脂产生细胞的丧失，与认知高度相关老年人口的赤字。少突胶质细胞前体细胞（OPC）分化发生在白质中慢性缺氧的富集区域，但不足以修复白质。因此，合法的策略 VCID中提高功能结果是通过保护少突胶质细胞和通过促进少突胶质细胞再生。脂联素是血液中最丰富的脂肪因子，在中枢神经系统病理中起着至关重要的作用。我们报告了脂联素对认知功能很重要，并减少了不对称中海马神经元丧失 VCID的常见颈动脉狭窄（ACA）小鼠模型。但是，脂联素对白色的影响 VCID后的物质完整性未知。为了填补这一重要空白，我们最近评估了功能影响年轻小鼠ACA后白质成分上的脂联素的脂肪蛋白。我们的飞行员数据表明脂联素缺乏降低了白质完整性，并损害ACA后轴突传导42D。脂联蛋白淘汰（KO）小鼠表现出更大的少突胶质细胞损失和少突胶质细胞再生。相反，治疗与脂联素受体的小分子激动剂Adiporon一起改善了长期的白质完整性和 ACA后最多可达到42D的高级认知功能。我们观察到脂联素受体1（adipor1）在体内高胶质细胞和小胶质细胞上高度表达。进一步的体外数据表明adiporon保护通过AMPK激活培养的少突胶质细胞针对氧/葡萄糖剥夺。阿迪波龙也是如此增强小胶质细胞增多症，并促进小胶质细胞的寡聚能力。基于这些有希望的数据，我们将检验脂联素促进结构和功能性白质完整性并改善慢性脑灌注灌注的神经功能 - 通过双重机制诱导的VCID：1）通过AMPK激活增强少突胶质细胞的存活，而2）促进具有较高少突胶能力的修复小胶质细胞表型。三个具体目标将进行测试。目标1：测试脂联素是否以AMPK依赖性的方式保护少突胶质细胞以改善白色 ACA后的物质完整性。目标2：测试脂联素是否会将小胶质细胞转移到修复表型中增强ACA后OPC分化。 AIM 3：测试Adiporon治疗是否增强了白质完整性并改善了两性老年小鼠ACA后的长期认知功能。这些研究将浮出水面作为脂联素作为改善VCID白质完整性的关键介体。积极的结果也会加速在VCID老年男性和女性中，Adiporon作为临床治疗的发展。