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