Microglial heparan sulfate in the modulation of APOE function and neurodegeneration

小胶质细胞硫酸乙酰肝素调节 APOE 功能和神经退行性变

• 批准号: 10555329
• 负责人: YU YAMAGUCHI
• 金额: $ 58.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555329
• 关键词: ATP binding cassette transporter 1; Ablation; Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid deposition; Animals; Apolipoprotein E; Attention; Behavioral; Binding; Binding Proteins; Brain; Brain Pathology; Cell surface; Charge; Cholesterol; Code; Core Protein; Data; Dementia; Development; Excision; Exhibits; Extracellular Matrix; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Goals; Heparan Sulfate Proteoglycan; Heparin; Heparitin Sulfate; Heparitin sulfotransferase; Human; Human Genetics; Immunomodulators; Impaired cognition; In Vitro; Late Onset Alzheimer Disease; Ligands; Link; Lipids; Maintenance; Mediating; Medical; Microglia; Molecular; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurons; Pathway interactions; Phenotype; Play; Polysaccharides; Process; Protein Isoforms; Proteins; Recurrent disease; Regulation; Relative Risks; Reporting; Research; Research Priority; Resistance; Risk; Risk Factors; Role; Senile Plaques; Series; Signal Transduction; Sulfate; Surface; Synapses; TREM2 gene; Variant; Woman; apolipoprotein E-3; apolipoprotein E-4; cationic antimicrobial protein CAP 37; cholesterol transporters; experimental study; functional genomics; genetic association; genetic risk factor; genomic data; glial activation; glycosylation; immunoregulation; in vivo; insight; mouse model; neuroinflammation; novel; presenilin-1; receptor; response; sugar; tau Proteins; therapeutic target

Heparan sulfate (HS), a sulfated glycan expressed at the cell surface and in extracellular matrix, has long attracted attention as a putative factor involved in Alzheimer's disease (AD), based on circumstantial evidence from in vitro and clinicopathological studies. Nevertheless, the functional significance of HS in AD, especially in the late-onset type (LOAD) that comprises more than 90% of AD cases, is elusive. Recent human genomic studies implicate ApoE and microglia as dominant contributors to neurodegeneration in LOAD. The APOE gene is the strongest known genetic risk factor for LOAD. Accumulating data indicate that ApoE proteins exert immunomodulatory effects on microglia, and that this function of ApoE is at least partly mediated by the TREM2 receptor, another AD risk factor that is expressed by microglia. Among the three human APOE alleles, the APOE4 allele confers an increased risk for LOAD, while the APOE2 allele confers a decreased risk relative to the more common APOE3 allele. The molecular basis of these allele- specific risk variations is one of the key unanswered issues in AD research. In this context, it is interesting to note that ApoE proteins bind HS in an isoform-specific manner — ApoE4 exhibits 2- to 3-fold greater affinity for HS than ApoE2 and ApoE3, thus apparently correlating with their relative AD risks. Furthermore, a recent report regarding the unique case of a Columbian woman, who carries a highly detrimental PSEN1E280A mutation, suggests that her APOE3 "Christchurch" mutation, which abolishes the affinity of ApoE3 for HS, confers strong protection against neurodegeneration and cognitive impairment. Also suggesting the functional involvement of HS in LOAD are recurrent reports of genetic association of HS sulfotransferase genes with LOAD. In a series of preliminary studies, we have obtained multiple pieces of evidence suggesting that the strong interaction of HS with ApoE4, relative to its interactions with ApoE2 and ApoE3, is the key underlying mechanism by which ApoE4 exerts a detrimental effect on the brain. Significantly, we have found that haploinsufficient reduction in HS expression leads to the mitigation of synapse loss and microglial activation in the PS19 TauP310S mouse model. We hypothesize that HS plays a critical role in mediating the ApoE4 effect on microglial response and function, and that the detrimental effect of the APOE4 allele is mainly due to its stronger interaction with the 3-O sulfate-rich HS species expressed in microglia. We will: (1) determine the role of HS in ApoE-TREM2 interaction and signaling in microglia; (2) determine the role of microglial HS in ApoE/ABCA1-mediated cholesterol efflux; and (3) examine in vivo effects of microglial HS on brain pathology and function in AD mouse models. This research will provide entirely novel insights into the role of HS in microglia, and moreover, into long-term questions regarding the isoform-specific risk of APOE variants. Successful completion of this project will reveal the ApoE4-HS interaction as a promising therapeutic target for reducing AD risk in APOE4 carriers.

硫酸乙酰肝素（HS）是一种在细胞表面和细胞外基质中表达的硫酸化聚糖， 引起注意，作为一个假定的因素参与阿尔茨海默氏病（AD），根据间接 来自体外和临床病理学研究的证据。然而，HS在 AD，特别是在包括超过90%的AD病例的晚发型（LOAD）中，是难以捉摸的。最近 人类基因组研究暗示ApoE和小胶质细胞是神经变性的主要贡献者， 即可.载脂蛋白E基因是已知的最强的遗传风险因素负载。累积数据显示 ApoE蛋白对小胶质细胞发挥免疫调节作用，ApoE的这种功能至少 部分由TREM 2受体介导，TREM 2受体是另一种由小胶质细胞表达的AD风险因子。中 三个人类APOE等位基因，APOE 4等位基因赋予LOAD的风险增加，而APOE 2等位基因 相对于更常见的APOE 3等位基因，这些等位基因的分子基础- 特定风险差异是AD研究中尚未解决的关键问题之一。在这种背景下， 注意到ApoE蛋白以同种型特异性方式结合HS-ApoE 4表现出2至3倍的高亲和力， 与HS的亲和力高于ApoE 2和ApoE 3，因此与其相对AD风险明显相关。此外，委员会认为， 最近一份关于一名哥伦比亚妇女的独特案例的报告， PSEN 1 E280 A突变，表明她的APOE 3“基督城”突变，这废除了亲和力， ApoE 3对HS具有很强的保护作用，可防止神经变性和认知障碍。也 提示HS在LOAD中的功能参与是HS遗传关联的反复报道 具有LOAD的磺基转移酶基因。在一系列的初步研究中，我们已经获得了多块 有证据表明，相对于HS与ApoE 2的相互作用，HS与ApoE 4的相互作用较强， 和ApoE 3，是ApoE 4对大脑产生有害影响的关键潜在机制。 值得注意的是，我们已经发现HS表达的单倍不足减少导致了HS表达的减轻。 PS19 TauP 310 S小鼠模型中的突触丢失和小胶质细胞活化。我们假设HS扮演着 在介导ApoE 4对小胶质细胞反应和功能的影响中起关键作用， APOE 4等位基因的作用主要是由于其与富含3-O硫酸盐的HS物种的更强的相互作用 在小胶质细胞中表达。我们将：（1）确定HS在ApoE-TREM 2相互作用和信号传导中的作用， （2）确定小胶质细胞HS在ApoE/ABCA 1介导的胆固醇流出中的作用;和（3） 在AD小鼠模型中检查小胶质细胞HS对脑病理学和功能的体内作用。这 这项研究将为HS在小胶质细胞中的作用提供全新的见解，此外， 关于APOE变体的异构体特异性风险的问题。该项目的成功完成将 揭示了ApoE 4-HS相互作用作为降低APOE 4携带者AD风险的有前景的治疗靶点。