White Matter Injury and Repair in Vascular Cognitive Impairment and Dementia

血管性认知障碍和痴呆（VCID）是第二种最常见的痴呆类型。没有保护 或疾病修饰策略可用于逆转或停止VCID。VCID的主要特征是白色物质 病理学，包括脱髓鞘和髓鞘产生细胞的损失，这与认知功能高度相关。 老年人口的赤字。少突胶质前体细胞（OPC）分化发生在白色物质中 在慢性缺氧时富集区域，但不足以用于白色修复。因此，一个合法的战略， VCID中改善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，在中枢神经系统疾病中起着重要作用。我们已经报道 脂联素对认知功能很重要，可减少非对称性海马神经元的丢失， 颈总动脉狭窄（ACAS）小鼠VCID模型。然而，脂联素对白色 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 脂联素对幼龄小鼠ACAS后白色物质成分的影响。我们的试验数据显示脂联素 ACAS后42天，缺乏可降低白色物质的完整性并损害轴突传导。脂联素基因敲除 (KO)小鼠表现出更大的少突胶质细胞损失和更少的少突胶质细胞再生。相反，治疗 adipoRon是脂联素受体的小分子激动剂，可改善长期白色物质的完整性， 导致ACAS后42天的上级认知功能。我们观察到脂联素受体1（adipoR 1） 在体内少突胶质细胞和小胶质细胞上高度表达。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AMPK激活对抗氧/葡萄糖剥夺。AdipoRon也 增强小胶质细胞的吞噬作用并促进小胶质细胞的少突生成能力。 基于这些有希望的数据，我们将测试脂联素促进结构和功能的新假设。 功能性白色物质完整性，改善慢性脑灌注不足的神经功能- 通过双重机制诱导VCID：1）通过AMPK活化增强少突胶质细胞存活，和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 得到考验目的1：检测脂联素是否以AMPK依赖性方式保护少突胶质细胞，以改善白色 ACAS后的物质完整性。目的2：检测脂联素是否使小胶质细胞向修复性表型转变， 增强ACAS后的OPC分化。目的3：测试adipoRon治疗是否增强了白色物质的完整性 并改善老年小鼠ACAS后的长期认知功能。这些研究将揭示 脂联素作为一种关键介质，以改善白色物质的完整性，在VCID。积极的结果也将加速 开发adipoRon作为老年男性和女性VCID的临床治疗。

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.