Role of Microglia in Neurodegeneration -Effect of ApoE

小胶质细胞在神经退行性变中的作用 - ApoE 的作用

基本信息

批准号：
10370582
负责人：
MARTIN Joseph SADOWSKI
金额：
$ 72.51万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370582
关键词：
ATP binding cassette transporter 1 Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Astrocytes Attenuated Behavior Behavior Control Brain Cells Characteristics Complement Cre-LoxP Creutzfeldt-Jakob Syndrome Deposition Disease Event Gene Expression Genes Genotype Grant High Density Lipoproteins Homeostasis Homozygote Human Impairment Inflammation Inflammatory Inflammatory Response Investigation Knock-out Lesion Link Lipids Mediating Microglia Modeling Molecular Conformation Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Neurons Opsonin Pathogenesis Pathology Phagocytes Phagocytosis Phenotype Play PrP PrPSc Proteins Prion Diseases Prions Property Protein Isoforms Proteomics RNA Risk Factors Role Scrapie Source TREM2 gene Tauopathies Therapeutic Time Tissues Up-Regulation Ursidae Family Work abeta accumulation abeta deposition apolipoprotein E-4 base chemokine connectome cytokine high risk lipid metabolism metaplastic cell transformation mind control misfolded protein mouse model nano-string neurodegenerative phenotype neuroinflammation neuron loss neurotoxic overexpression particle phenotypic biomarker protein expression receptor response transcriptome sequencing transcriptomics

项目摘要

Project Summary Like Alzheimer's disease, prion diseases (prionoses) are conformational disorders, in which deposition of misfolded proteins is accompanied by microglia neurodegenerative phenotype (MGnD) displaying mixed phagocytic and inflammatory properties. Prion mouse models with misfolded protein driven neurodegeneration and activated glia response can be used to uncover Alzheimer's disease relevant pathomechanisms. APOE ε4 allele is the foremost risk factor in sporadic Alzheimer's disease, increasing its odds by 3 and 15-fold in hetero and homozygotes, respectively. APOE encodes apolipoprotein (apo) E, which controls brain lipid homeostasis and modulates Alzheimer's disease risk through isoform-specific effect on clearance and deposition of soluble Aβ. ApoE is expressed by astrocytes in form of apoE/HDLs and also by MGnD as lipid-poor particles. Differential contributions of these two apoE pools to MGnD properties remain unclear. While lipidated apoE may facilitate clearance of misfolded proteins, expression of lipid-poor apoE by MGnD is linked to their pro-inflammatory properties, which also are differentially controlled by APOE genotype. In prionoses, accumulation of toxic PrPSc protein is the culprit of pathogenesis. Microglia undergo activation early in the course of disease and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc has a disease-limiting effect, microglia-driven neuroinflammation is deleterious to neurons. Involvement of apoE in prion pathogenesis has not been established, though there is evidence for ~2-fold higher risk of sporadic Creutzfeldt-Jakob disease (CJD) in ε4 carriers. Our preliminary work shows increased brain apoE level in prion infected mice along with reduced apoE expression in astrocytes and increased expression in activated microglia. The overall effect of apoE in prionoses is beneficial as global Apoe KO exacerbates prion pathology by aggravating the vicious cycle of neuronal death and neuroinflammation. In Apoe-/- mice, clearance of PrPSc and dying neurons by MGnD becomes inefficient while neuronal debris exaggerate MGnD phenotype, release of inflammatory cytokines, and induce A1 neurotoxic astrocytes. Our studies also suggest, apoE effect in prionoses is isoform dependent. ε4/ε4 targeted replacement (TR) mice have shorter disease incubation time, increased pathology load and microglia hyperactivation compared to ε3/ε3 and ε2/ε2 mice. This preliminary work led us to hypothesize 1) apoE involvement in prion pathogenesis is by control of microglia response to PrPSc mediated neurodegeneration; 2) apoE-based approaches have therapeutic merit in prionoses; and 3) effect of apoE in human prionoses is isoform dependent. These hypotheses shall be explored in grant's specific aims. Aim I will assess the role of astrocyte vs. microglia-expressed apoE on PrPSc mediated neurodegeneration in mice with cell-specific conditional Apoe knock out. Aim II will assess whether regulating lipidation level of astrocytic and microglial apoE and the total brain apoE level modulates neurodegeneration. Aim III will explore effects of APOE genotype on microglia activation phenotype in prion infected APOE TR mice and in sporadic CJD and Alzheimer's disease patients.

项目摘要像阿尔茨海默氏病一样错误折叠的蛋白伴随着小胶质细胞神经退行性表型（MGND），显示混合吞噬和炎症特性。具有错误折叠蛋白驱动神经退行性的Prion小鼠模型活化的神经胶质反应可用于发现阿尔茨海默氏病有关的病理机理。 apoeε4 等位基因是零星阿尔茨海默氏病的首要危险因素，其差异增加了3至15倍和纯合子。 APOE编码载脂蛋白（APO）E，该E控制脑脂质稳态并通过同工型特异性对清除和可溶性沉积来调节阿尔茨海默氏病风险 Aβ。 APOE用APOE/HDLS形式的星形胶质细胞表达，也用MGND作为脂质贫困颗粒表达。微分这两个APOE池对MGND性质的贡献尚不清楚。而脂化的apoE可能有助于清除错误折叠的蛋白质，MGND的脂肪贫苦APOE的表达与促炎性有关属性也由APOE基因型也不同。在优先级，有毒PRPSC的积累蛋白质是发病机理的罪魁祸首。在疾病和运动过程中，小胶质细胞接受激活在PRPSC介导的神经变性中相反的作用。虽然PRPSC的清除具有限制性效果，但小胶质细胞驱动的神经炎症对神经元有害。 APOE参与prion发病机理尽管有证据表明零星creutzfeldt-jakob病的风险高约2倍，但没有建立（CJD）在ε4载体中。我们的初步工作表明，主要感染小鼠的脑APOE水平升高在星形胶质细胞中的APOE表达降低，活化小胶质细胞中的表达增加。的总体效果隐私中的apoe是有益的，因为全球apoe ko通过加重恶性循环加剧了病毒病理神经元死亡和神经炎症。在apoe - / - 鼠标中，MGND的prPSC清除和垂死的神经元效率低下，而神经元碎片夸大了MGND表型，炎症细胞因子的释放和诱导A1神经毒性星形胶质细胞。我们的研究还表明，优先级的APOE效应是同工型依赖性的。 ε4/ε4 靶向替代（TR）小鼠的疾病孵育时间较短，病理负荷增加和小胶质细胞与ε3/ε3和ε2/ε2小鼠相比，过度激活。这项初步工作使我们假设1）APOE 参与Prion发病机理是通过控制对PRPSC介导的神经变性的小胶质细胞反应。 2）基于APOE的方法在优先级中具有治疗性优点； 3）APOE在人类优先级中的影响是同工型依赖。这些假设应在格兰特的具体目标中探讨。目的我将评估星形胶质细胞的作用与细胞特异性有条件APOE的小鼠中PRPSC介导的神经变性对小胶质细胞表达的APOE 昏死。 AIM II将评估标准胶质细胞和小胶质细胞APOE的脂化水平以及总数是否脑APOE水平调节神经变性。 AIM III将探索APOE基因型对小胶质细胞的影响主要感染APOE TR小鼠以及零星CJD和阿尔茨海默氏病患者的激活表型。