Redox-based Targeting of Cerebrovascular Dysfunction in AD

总结 越来越多的证据表明，脑血管功能障碍的共同发生， 阿尔茨海默病（AD）和血管疾病/疾病，从而表明了机制联系 其特征在于神经血管单位（NVU）的结构和功能完整性的丧失， 导致认知障碍在血管损伤的分子机制方面，实验 研究结果强调了氧化应激（OS）在诱导脑血管功能障碍中的主要作用， 这可能会因合并症如2型糖尿病（T2 DM）而加重。虽然OS长期以来 抗氧化剂被认为是神经退行性疾病的治疗靶点， 在临床上大多失败了。尽管有这种挫折，但另一种基于氧化还原的治疗方法 以氧化还原体内平衡为目标本身可能提供更好的选择。在这里，我们考虑和测试的假设， 增强内源性抗氧化机制，特别是在脆弱的血管系统中， 具有血管保护作用，因此，在有或没有共- 病态T2 DM。靶向的主要内源性氧化还原系统是硫氧还蛋白（TRX）-硫氧还蛋白相互作用 蛋白（Txnip）二人组，具有相互拮抗的氧化还原作用。 这些研究使用PDAPP Tg（J20）和Tg-SwDI小鼠与诱导型壁细胞（血管平滑肌细胞）杂交， 肌细胞/周细胞）报告细胞系，能够有效监测周细胞损失或其改变的血管 覆盖以及用于壁细胞中Txnip的Cre-loxP条件性缺失。将对Tg小鼠进行 非遗传性T2 DM模式，即，高脂饮食（HFD）和低剂量链脲佐菌素（STZ）的组合。 我们将采用基于氧化还原的双重策略，即，Trx 1肽模拟物（Aim 1）和遗传缺失的用途 壁细胞中Txnip的作用（目的2），以靶向该模型中的Trx氧化还原系统并评估其血管保护作用 在脑血管功能障碍的结构-功能指数改变方面的影响，包括BBB改变 血管通透性和血管反应性与认知结果相关。这项探索性研究的结果是 预期支持基于氧化还原的血管保护方法（包括可能使用脑非渗透剂 药物）治疗AD和血管对认知障碍的相关复杂病因学， 痴呆（VCID）。

Summary Increasing evidence suggests the common occurrence of cerebrovascular dysfunction shared between Alzheimer's disease (AD) and vascular conditions/diseases thereby suggesting a mechanistic link characterized by the loss of structural and functional integrity of the neurovascular unit (NVU) in turn contributing to cognitive impairment. In terms of molecular mechanisms of vascular damage, experimental findings emphasize the major role that oxidative stress (OS) plays in inducing cerebrovascular dysfunction, which could be exacerbated by co-morbid conditions such as type-2 diabetes (T2DM). Although OS has long been considered a therapeutic target in neurodegenerative diseases in general, antioxidant therapies so far have mostly failed clinically. This setback notwithstanding, an alternative redox-based therapeutic approach targeting redox homeostasis per se might offer a better option. Here, we consider and test the hypothesis that boosting endogenous anti-oxidant mechanisms particularly within the vulnerable cerebrovasculature might have a vasculoprotective role and hence, improved cognitive outcome in a model of AD with or without co- morbid T2DM. The major endogenous redox system targeted is the Thioredoxin (TRX)-Thioredoxin-interacting protein (Txnip) duo with their mutually antagonistic redox roles. The studies use PDAPP Tg (J20) and Tg-SwDI mice crossed with an inducible mural cell (vascular smooth muscle cell/pericyte) reporter line to enable efficient monitoring of pericyte loss or their altered vascular coverage as well as for Cre-loxP conditional deletion of Txnip in mural cells. The Tg mice will be subjected to a non-genetic T2DM paradigm i.e., a combination of high fat diet (HFD) and low-dose of streptozotocin (STZ). We will employ a redox-based dual strategy i.e., the use of a Trx1 peptidomimetic (Aim 1) and genetic deletion of Txnip in mural cells (Aim 2) to target the Trx redox system in this model and evaluate their vasculoprotective effects in terms of altered structure-function indices of cerebrovascular dysfunction including altered BBB permeability and vasoreactivity correlated with cognitive outcome. The findings of this exploratory study are expected to support a redox-based vasculoprotective approach (including potential use of brain non-penetrant drugs) to treat AD and the related complex etiology of `vascular contributions to cognitive impairment and dementia (VCID)'.