Aβ蛋白沉积在慢性缺血性脑白质病变导致认知功能减退中的作用及机制研究

Chronic ischemic white matter changes (WMC) are important substrates for cognitive decline in the elderly. However, the mechanism of WMC induced cognitive decline was still unknown. Excessive amyloid β (Aβ) deposition is the key pathway for Alzheimer’s disease (AD). Lines of evidence have demonstrated that Aβ deposition could exist in subcortical ischemic vascular dementia. Our previous studies have also shown that Aβ deposition was associated with cognitive decline in WMC patients using 11C PIB PET, and the pattern of Aβ deposition was similar to that of AD patient. Furthermore, our preliminary investigations of bilateral carotid artery stenosis (BCAS) model found that Aβ 1-40 reactivity was detected in WMC mice and consequently cognitive decline occurred at 2 months after BCAS. These findings suggested that WMC may induce cognitive decline through Aβ deposition. In this context, we aimed to investigate spatial and temporal distribution character of Aβ deposition on BCAS model, and the potential mechanism of neurovascular unit dysfunction on Aβ deposition, as well as the relationship of progression of Aβ deposition with WMC progression and cognitive decline using 11C PIB PET imaging. It may not only provide novel insights for WMC induced cognitive decline, but also explore new strategies for prevention and treatment of Aβ deposition and cognitive decline.

慢性缺血性脑白质病变（WMC）是老年人认知功能减退的重要病因，但其中机制仍不清楚。我们既往研究发现：WMC患者的Aβ沉积量与认知功能减退密切相关，并且WMC患者的Aβ沉积模式可与AD患者类似。我们还发现：实验性WMC小鼠能够出现Aβ沉积和认知功能减退。这提示WMC可能通过引起Aβ沉积而导致认知功能减退。为此，本课题首先建立小鼠双侧颈动脉狭窄模型模拟WMC，利用形态学、分子生物学、神经化学等方法，观察WMC后Aβ沉积的时空分布特征，并进一步探讨神经血管单元破坏在Aβ沉积中的作用。另外，在临床人群中，以11C-PIB PET在体显影Aβ蛋白，前瞻性探索WMC进展与Aβ沉积的相关性，以及Aβ沉积是否介导WMC后认知功能减退。本课题旨在为WMC导致认知功能减退研究提供新的思路，也为Aβ蛋白沉积和认知功能减退的防治策略提供新的干预靶点。

慢性缺血性脑白质病变（WMC）是老年人认知功能减退的重要病因，但其中机制仍不清楚。Aβ淀粉样蛋白（Aβ）过度沉积是阿尔茨海默病（AD）发病机制的核心环节之一。我们既往研究发现在WMC患者中，Aβ沉积与患者认知功能减退密切相关，并且WMC患者的Aβ沉积模式与AD患者类似。实验性WMC小鼠能够出现Aβ沉积和认知功能减退。这提示WMC可能通过引起Aβ沉积而导致认知功能减退。本项目通过BCAS小鼠模型成功建立WMC模型，发现WMC模型中少突胶质细胞出现髓鞘化障碍并导致LDLR表达下降，及引起淀粉样蛋白沉积，明确了神经血管单元参与淀粉样蛋白Aβ沉积导致认知功能损害。动态入组了226例社区居民及100例脑卒中患者，建立并验证了血管性认知功能下降的神经心理学评价量表，明确了脑白质病变可以导致认知功能下降，脑白质病变与淀粉样蛋白沉积均为认知功能下降的独立预测因素。该研究为WMC导致认知功能减退研究提供新的思路，也为Aβ沉积和认知功能减退的防治策略提供新的干预靶点。