Targeting Neurovascular Dysfunction in AD

 描述(申请人提供)：在淀粉样蛋白靶向药物试验和免疫疗法失败后，最近的努力针对阿尔茨海默病(AD)的广泛替代机制，特别是血管功能障碍。我们研究的总体目标是将脑血管功能障碍定义为2型糖尿病(T2 DM)和AD等心脏代谢紊乱之间的机制联系，并作为AD治疗中血管保护策略的潜在靶点。本项目利用非遗传性T2 DM的阿尔茨海默病小鼠模型，显示淀粉样蛋白沉积加速并伴有认知障碍。该方法使用创新的技术和策略，包括使用双光子成像，重点关注血管变化(即周细胞丢失/损伤、星形胶质细胞末端和与血管淀粉样蛋白增加相关的血脑屏障破坏)和反应，即改变的功能性充血(脑血流)和血管扩张，可能导致代谢/突触功能障碍和认知能力下降。在一种治疗方法中，我们将测试一种新型的载脂蛋白AI模拟肽(5A)在糖尿病AD模型中的疗效，该模拟肽具有血管保护特性。这些研究的结果将为AD的血管假说提供有力和直接的支持，并进一步建议限制AD发病的血管诱因的新疗法。

 DESCRIPTION (provided by applicant): In the wake of failed amyloid-targeted drug trials and immune therapies, recent efforts are directed towards a broad range of alternative mechanisms of Alzheimer's disease (AD) including, in particular vascular dysfunction. The overall goal of our research is to define cerebrovascular dysfunction as a mechanistic link between cardiometabolic disorders such as type 2-diabetes (T2DM) and AD and as a potential target for vasculoprotective strategies in AD treatment. The present project utilizes a mouse model of AD with non-genetically induced T2DM that shows accelerated amyloid deposition with cognitive impairment. The approach uses innovative techniques and strategies including the use of 2-photon imaging focused on vascular changes (i.e., pericyte loss/injury, astrocyte endfeet and blood brain barrier disruption correlated with increased vascular amyloid) and responses i.e., altered functional hyperemia (cerebral blood flow) and vasodilation potentially leading to metabolic/synaptic dysfunction and cognitive decline. In a therapeutic approach, we will test the efficacy of a novel Apo AI mimetic peptide (5A) with demonstrated vasculoprotective properties, in the diabetic AD model. The outcome of these studies should provide strong and direct support to the vascular hypothesis of AD and further suggest new therapeutics to limit vascular triggers of AD pathogenesis.