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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.

血管性认知障碍和痴呆(VCID)是第二种最常见的痴呆类型。无保护性或者，可以使用疾病修正策略来逆转或阻止VCID。VCID的一个主要特征是脑白质病理学，包括脱髓鞘和髓鞘产生细胞的丧失，这与认知高度相关老年人口的赤字。少突胶质前体细胞(OPC)分化见于白质在慢性缺氧的情况下，丰富的区域，但不足以修复脑白质。因此，一个合法的战略是改善VCID的功能结局是通过保护少突胶质细胞和通过促进少突胶质细胞再生。脂联素是血液中含量最丰富的脂肪因子，在中枢神经系统的病理过程中起着至关重要的作用。我们已经报道了脂联素对认知功能有重要作用，可减少不对称痴呆患者海马神经元的丢失。颈总动脉狭窄(ACAS)小鼠VCID模型。然而，脂联素对白色皮肤的影响 VCID后的物质完整性尚不清楚。为了填补这一重要空白，我们最近评估了功能影响脂联素对幼鼠ACAS后脑白质成分的影响。我们的试验数据显示，脂联素 ACAS后42d，缺氧性脑白质完整性降低，轴突传导受损。脂联素基因敲除 (KO)小鼠表现出较大的少突胶质细胞丢失和较少的少突胶质细胞再生。相比之下，治疗使用脂联素受体的小分子激动剂AdipoRon，可以改善长期脑白质完整性和导致ACAS后42d具有卓越的认知功能。我们观察到脂联素受体1(AdipoR1) 在体内高表达于少突胶质细胞和小胶质细胞。体外数据进一步表明，AdipoRon可以保护培养的少突胶质细胞通过激活AMPK对抗缺氧缺糖。AdipoRon还增强小胶质细胞的吞噬功能，促进小胶质细胞的少突胶质形成能力。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的新假设。慢性脑低灌注症患者脑白质功能完整并改善神经功能 VCID的诱导有两种机制：1)通过激活AMPK提高少突胶质细胞的存活；2) 促进具有高少突胶质细胞生成能力的修复性小胶质细胞表型。三个具体目标将接受测试。目的1：测试脂联素是否以AMPK依赖的方式保护少突胶质细胞以改善白质 ACAS后的物质完整性。目的2：测试脂联素是否使小胶质细胞向修复表型转变增强ACAS后OPC的分化。目标3：测试AdipoRon治疗是否增强脑白质完整性并改善ACAS后老年小鼠的长期认知功能，无论性别。这些研究将揭示脂联素作为改善VCID患者脑白质完整性的关键介质。积极的结果也会加速 AdipoRon作为老年男性和女性VCID临床治疗的发展。