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

硫酸乙酰肝素蛋白多糖在脑血管清除淀粉样蛋白-β 和阿尔茨海默氏病中的作用

基本信息

  • 批准号:
    10301892
  • 负责人:
  • 金额:
    $ 179.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-15 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

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.
项目摘要 阿尔茨海默病(Alzheimer's disease,AD)是一种进行性脑退行性疾病, 伴随早期神经血管改变和错误折叠的淀粉样蛋白-β(Aβ)和tau蛋白在脑中的积累。在 目前,没有有效的治疗方法可以减缓或停止AD的进展。因此,揭露小说 控制AD发病机制的机制可能会促进更有效的治疗药物的开发, 治疗这种毁灭性疾病的策略。越来越多的证据表明, Ab在脑实质和脑血管(CBV)中的表达是导致其他AD相关疾病的关键事件。 病理学散发性AD患者的动力学研究表明,Aβ清除缺陷,而不是Aβ Aβ在脑内的聚集和聚集是关键的。然而,分子 这种Aβ蓄积的基础仍然知之甚少。我们的初步研究表明乙酰肝素 硫酸盐(HS),一种硫酸多糖,其关键地介导细胞-细胞和细胞-基质相互作用, 信号传导在AD患者的CBV中强烈降低。在这个应用程序中,我们将测试我们的新假设, CBV中表达的HS通常促进Ab从脑中清除,并且这种功能被破坏 在AD中,导致Ab清除受损。从机制上讲,我们假设HS保持CBV的完整性, 在LRP 1介导的Ab清除中作为共受体发挥作用,并促进血管周围Ab消除。我们将 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Ab清除中的作用,并检验增加bEC-HS表达使Ab正常化的假设 清除以减轻AD发病机制。2.阐明bEC-HS作用的分子机制 在脑Ab清除和AD发病机制中的作用。3.阐明脑血管平滑肌细胞(bVSMC)的作用- HS在脑Ab清除和AD发病机制中的作用这些拟议的研究利用了新的和已建立的 遗传、细胞、scRNA-seq和生物化学方法与人类AD标本和AD 小鼠模型。本研究的结果有望阐明在CBV中表达的HS作为一种关键的 分子介导的脑Ab清除和降低的CVS-HS表达加重AD,并将提供 体内证据证明了增加bEC-HS是缓解AD的有效干预措施 发病机制

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Application of a Mutant Cell Library to Determine the Structure-Function Relationship of Heparan Sulfate in Facilitating FGF2-FGFR1 Signaling.
应用突变细胞库确定硫酸乙酰肝素促进 FGF2-FGFR1 信号传导的结构功能关系。
Fucoidans inhibited tau interaction and cellular uptake
  • DOI:
    10.1016/j.carbpol.2022.120176
  • 发表时间:
    2022-10-05
  • 期刊:
  • 影响因子:
    11.2
  • 作者:
    Jin,Weihua;Lu,Chenghui;Zhang,Fuming
  • 通讯作者:
    Zhang,Fuming
Structural characteristics of Heparan sulfate required for the binding with the virus processing Enzyme Furin.
  • DOI:
    10.1007/s10719-021-10018-8
  • 发表时间:
    2022-06
  • 期刊:
  • 影响因子:
    3
  • 作者:
    Zeng J;Meng Y;Chen SY;Zhao G;Wang L;Zhang EX;Qiu H
  • 通讯作者:
    Qiu H
Cell-Free Extracellular Vesicles Derived from Human Bone Marrow Endothelial Progenitor Cells as Potential Therapeutics for Microvascular Endothelium Restoration in ALS.
  • DOI:
    10.1007/s12017-020-08607-1
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    Garbuzova-Davis S;Willing AE;Ehrhart J;Wang L;Sanberg PR;Borlongan CV
  • 通讯作者:
    Borlongan CV
Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1.
在阿尔茨海默氏病大脑中,硫酸盐硫酸盐硫酸盐的增加与遗传风险基因HS3ST1有关。
  • DOI:
    10.1126/sciadv.adf6232
  • 发表时间:
    2023-05-26
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
    Wang, Zhangjie;Patel, Vaishali N.;Song, Xuehong;Xu, Yongmei;Kaminski, Andrea M.;Doan, Vivien Uyen;Su, Guowei;Liao, Yien;Mah, Dylan;Zhang, Fuming;Pagadala, Vijayakanth;Wang, Chunyu;Pedersen, Lars C.;Wang, Lianchun;Hoffman, Matthew P.;Gearing, Marla;Liu, Jian
  • 通讯作者:
    Liu, Jian
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Lianchun Wang其他文献

Lianchun Wang的其他文献

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{{ truncateString('Lianchun Wang', 18)}}的其他基金

Using CRISPR-Cas9 technology to develop a mutant cell library for heparan sulfate structure-function study
利用CRISPR-Cas9技术开发硫酸乙酰肝素结构功能研究突变细胞库
  • 批准号:
    8985421
  • 财政年份:
    2015
  • 资助金额:
    $ 179.38万
  • 项目类别:
MOLECULAR MECHANISMS UNDERLYING HEPARIN-INDUCED LEUKOCYTOSIS
肝素诱导白细胞增多的分子机制
  • 批准号:
    8361868
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
ROLE OF ENDOTHELIUM ON MYOCARDIAL INFARCTION INJURY RESPONSE
内皮细胞对心肌梗塞损伤反应的作用
  • 批准号:
    8361867
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
REGULATORY MECHANISM OF HEPARIN/HEPARAN SULFATE ON VEGF SIGNALING
肝素/硫酸乙酰肝素对 VEGF 信号传导的调节机制
  • 批准号:
    8361866
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
REGULATORY ROLE OF HEPARAN SULFATE ON SLIT3/ROBO-MEDIATED ANGIOGENESIS
硫酸乙酰肝素对 SLIT3/ROBO 介导的血管生成的调节作用
  • 批准号:
    8361870
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
REGULATORY ROLE OF HEPARAN SULFATE EMBRYONIC STEM CELL BIOLOGY
硫酸乙酰肝素胚胎干细胞生物学的调节作用
  • 批准号:
    8361871
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
GENERATION OF HEPARAN SULFATE MUTANT MOUSE ENDOTHELIAL CELL LINES
硫酸乙酰肝素突变型小鼠内皮细胞系的产生
  • 批准号:
    8361864
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
NEW STRATEGIES TO DETERMINE STRUCTURE-FUNCTION RELATIONSHIPS OF HS CO-RECEPTORS
确定 HS 共受体结构-功能关系的新策略
  • 批准号:
    8361865
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
CHARACTERIZATION OF GLYCOSAMINOGLYCANS BY 15N NMR & IN VIVO ISOTOPIC LABELING
通过 15N NMR 表征糖胺聚糖
  • 批准号:
    8361872
  • 财政年份:
    2011
  • 资助金额:
    $ 179.38万
  • 项目类别:
Heparan sulfate proteoglycan interacts with Slit/Robo to regulate angiogenesis
硫酸乙酰肝素蛋白多糖与 Slit/Robo 相互作用调节血管生成
  • 批准号:
    8470214
  • 财政年份:
    2009
  • 资助金额:
    $ 179.38万
  • 项目类别:
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