Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease

项目总结 阿尔茨海默病(AD)是一种进行性脑退行性疾病，是一种与痴呆有关的疾病 早期神经血管改变和错误折叠的淀粉样蛋白β(Aβ)和tau在脑内积聚。在… 目前，还没有有效的治疗方法来减缓或阻止AD的进展。因此，揭开小说 控制AD发病机制可能会促进更有效的治疗方法的发展 治疗这种毁灭性疾病的策略。越来越多的证据表明，这种积累和聚集 脑实质和脑血管(CBV)中的抗体是导致其他AD相关的关键事件 病理学。散发性AD患者的动力学研究表明，Aβ清除错误，而不是Aβ 过量生产，是Aβ在大脑中积累和聚集的关键。然而，分子 这种β积累的基础仍然鲜为人知。我们的初步研究表明，肝素 硫酸盐(HS)是一种硫化多糖，它关键地介导细胞-细胞和细胞-基质相互作用 在AD患者的CBV中，信号强度显著降低。在本应用程序中，我们将测试我们的新假设 在CBV中表达的HS通常有助于将抗体清除出大脑，这种功能被破坏 在AD中，导致抗体清除受损。从机制上讲，我们假设HS保持CBV完整性， 在LRP1介导的抗体清除中起辅助受体的作用，并促进血管周围抗体的清除。我们会 追求以下3个具体目标来严格检验我们的假设：1.阐明脑内皮细胞的作用 细胞(BEC)HS在抗体清除中的作用并检验BEC-HS表达增加可使抗体正常化的假设 清除以减轻AD的发病机制。2.阐明BEC-HS作用的分子机制 在脑抗体清除和AD发病机制中的作用。3.阐明脑血管平滑肌细胞(BVSMC)- HS在脑抗体清除和AD发病机制中的作用这些拟议的研究既利用了新的，也利用了现有的 结合人类AD标本和AD的遗传学、细胞学、scRNA-seq和生化方法 老鼠模型。这项研究的结果有望说明在CBV中表达HS是一个关键 分子介导脑抗体清除和CVS-HS表达减少加剧AD，并将提供 增加BEC-HS是缓解AD的有效干预原则的活体证据 发病机制。

PROJECT SUMMARY Alzheimer`s disease (AD) is a progressive degenerative disease of the brain, a dementing illness associated with early neurovascular changes and the accumulation of misfolded amyloid-β (Aβ) and tau in the brain. At present, no effective treatment is available to slow or halt the progression of AD. Hence, uncovering novel mechanisms that govern AD pathogenesis may advance the development of more effective therapeutic strategies to treat this devastating disease. Mounting evidence suggests that the accumulation and aggregation of Ab in brain parenchyma and cerebral blood vessels (CBVs) is a key event leading to other AD-related pathologies. Kinetic studies in patients with sporadic AD indicate that faulty Aβ clearance, rather than Aβ overproduction, is critical for accumulation and aggregation of Aβ in brain. However, the molecular underpinnings of such Aβ accumulation remain poorly understood. Our preliminary studies indicate that heparan sulfate (HS), a type of sulfated polysaccharide that critically mediates cell-cell and cell-matrix interaction and signaling, is strongly reduced in CBVs of AD patients. In this application, we will test our novel hypothesis that HS expressed in CBVs normally facilitates the clearance of Ab out of the brain and that such function is disrupted in AD, leading to impaired Ab clearance. Mechanistically, we hypothesize that HS maintains CBV integrity, functions as a co-receptor in LRP1-mediated Ab clearance and facilitates perivascular Ab elimination. We will pursue the following 3 specific aims to rigorously test our hypothesis: 1. Elucidate the roles of brain endothelial cell (bEC) HS in Ab clearance and test the hypothesis that increasing bEC-HS expression normalizes Ab clearance to mitigate AD pathogenesis. 2. Delineate the molecular mechanisms underlying the roles of bEC-HS in brain Ab clearance and AD pathogenesis. 3. Elucidate the roles of brain vascular smooth muscle cell (bVSMC)- HS in brain Ab clearance and AD pathogenesis. These proposed studies exploit both novel and established genetic, cellular, scRNA-seq and biochemical approaches in conjunction with human AD specimen and AD mouse models. The results of this study are expected to illuminate HS expressed in CBVs serves as a key molecule to mediate brain Ab clearance and decreased CVS-HS expression exacerbates AD, and will provide in vivo evidence for the proof of principle that increasing bEC-HS is an effective intervention to mitigate AD pathogenesis.