Role of Microglia in Neurodegeneration -Effect of ApoE

项目摘要 与阿尔茨海默氏病一样，朊病毒病（朊病毒病）是构象障碍，其中朊病毒的沉积是一种代谢性疾病。 错误折叠的蛋白质伴随着小胶质细胞神经退行性表型（MGnD）， 吞噬和炎症特性。具有错误折叠蛋白质驱动的神经变性的朊病毒小鼠模型 并且激活的胶质反应可用于揭示阿尔茨海默病相关的病理机制。APOE ε4 等位基因是散发性阿尔茨海默病的首要危险因素，在异源性阿尔茨海默病中， 和纯合子。载脂蛋白E编码载脂蛋白E，控制脑脂质稳态 并通过对可溶性蛋白质的清除和沉积的同种型特异性作用来调节阿尔茨海默病的风险。 Aβ。ApoE由星形胶质细胞以apoE/HDL的形式表达，并且也由MGnD作为贫脂颗粒表达。微分 这两个apoE池对MGnD性质的贡献仍然不清楚。虽然脂化apoE可能有助于 通过清除错误折叠的蛋白质，通过MGnD表达脂质贫乏的apoE与它们的促炎性相关。 特性，这也是由APOE基因型差异控制。在朊病毒病中，有毒PrPSc的积累 蛋白质是致病的罪魁祸首。小胶质细胞在疾病过程的早期经历激活， 在PrPSc介导的神经变性中的相反作用。虽然PrPSc的清除具有疾病限制作用， 小胶质细胞驱动的神经炎症对神经元有害。apoE参与朊病毒的发病机制， 虽然有证据表明散发性Creutzfeldt-Jakob病的风险高出2倍，但尚未确定 (CJD)在ε4载体中。我们的初步工作表明，在朊病毒感染的小鼠中，随着沿着 星形胶质细胞中apoE表达减少，活化小胶质细胞中apoE表达增加。的整体效果 朊病毒病中的apoE是有益的，因为全球ApoE KO通过加重恶性循环而加重朊病毒病理 神经元死亡和神经炎症。在Apoe-/-小鼠中，MGnD对PrPSc和垂死神经元的清除 变得低效，而神经元碎片夸大了MGnD表型，释放炎性细胞因子， 诱导A1神经毒性星形胶质细胞。我们的研究还表明，apoE在朊病毒病中的作用是亚型依赖性的。ε4/ε4 靶向替代（TR）小鼠具有较短的疾病潜伏期、增加的病理负荷和小胶质细胞 与ε3/ε3和ε2/ε2小鼠相比，这项初步工作使我们提出了一个假设：载脂蛋白E 朊病毒发病机制的参与是通过控制小胶质细胞对PrPSc介导的神经变性的反应; 2） 基于apoE的方法在朊病毒病中具有治疗价值; 3）apoE在人类朊病毒病中的作用是同种型 依赖。这些假设将在格兰特的具体目标中进行探讨。目的探讨星形胶质细胞在肿瘤发生发展中的作用 vs.小胶质细胞表达的apoE对PrPSc介导的细胞特异性条件性ApoE小鼠神经变性的影响 击倒。目的二是评估调节星形胶质细胞和小胶质细胞apoE的脂化水平和总的 脑apoE水平调节神经变性。目的III探讨载脂蛋白E基因型对小胶质细胞的影响 在朊病毒感染的APOE TR小鼠和散发性CJD和阿尔茨海默病患者中的活化表型。

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.