Immune Injury of the Central Nervous System in Aged Humanized Transgenic apolipoprotein E Isoform-specific Knockin Mice

老年人源化转基因载脂蛋白E异构体特异性敲入小鼠中枢神经系统的免疫损伤

• 批准号: 280398872
• 负责人: Dr. Changjun Yin, Ph.D.
• 金额: --
• 依托单位: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280398872?language=en
• 关键词: Immune; Injury; Central; Nervous; System

Alzheimer disease (AD) and vascular dementia (VD) are the leading causes for dementia. Both forms of dementia share the same risk factors such as aging, hyperlipidemia, atherosclerosis, and the apolipoprotein E4 (Apoe4) genotype. However, relations of hyperlipidemia, atherosclerosis, apolipoprotein E genotype, and alterations in brain function during aging are not clear. A better understanding of the mechanisms how hyperlipidemia and apolipoprotein E (Apoe) isoforms affect the central nervous system (CNS) will be important to define molecular mechanisms of VD. Our unpublished data reveal hitherto unrecognized mechanisms of immune injury in aged Apoe-/- mouse brains: These include lipid accumulation in distinct hotspots of the brain parenchyma and the choroid plexus (CP), i.e. the structure that produces cerebrospinal fluid; formation of macrophage/microglia infiltrates in brain parenchyma; glia cell activation; activation of the complement pathway in CP and brain parenchyma; neuronal axon loss due to phagocytosis by macrophages; blood brain barrier (BBB) breakdown; and T/B plasma cell aggregates in the meninges and brain parenchyma. However, whether these changes are a direct result of hyperlipidemia or due to the absence of Apoe has not been determined. One way to address these fundamental issues is the use of humanized transgenic Apoe isoform-specific knockin mice. We hypothesize that hyperlipidemia may induce immune-mediated brain injury before impairment of cerebral blood flow causes strokes. We plan to (Aim1) define roles of hyperlipidemia and of apolipoprotein E isoforms in causing brain injury by using aged humanized Apoe4 knockin (KI) and Apoe3 KI mice; to (Aim2) analyze the effects of a complement inhibitor C5 RNAi (liver-specific) in aged Apoe-/- mice; and to construct (Aim3) microarray-based transcript atlases together with FACS analyses of aged Apoe-/- mouse brains, and in vitro biochemical apolipoprotein isoform binding and inhibition studies, and (Aim4) detection of lipid and inflammatory cell infiltration in the choroid plexus in aged hyperlipidemic dementia patients (non-stroke patients).

阿尔茨海默病（AD）和血管性痴呆（VD）是痴呆的主要原因。这两种形式的痴呆症都有相同的危险因素，如衰老、高脂血症、动脉粥样硬化和载脂蛋白 E4 (Apoe4) 基因型。然而，高脂血症、动脉粥样硬化、载脂蛋白E基因型和衰老过程中脑功能改变之间的关系尚不清楚。更好地了解高脂血症和载脂蛋白 E (Apoe) 亚型影响中枢神经系统 (CNS) 的机制对于定义 VD 的分子机制非常重要。我们未发表的数据揭示了老年 Apoe-/- 小鼠大脑中迄今为止未被认识的免疫损伤机制：其中包括脑实质和脉络丛（CP）（即产生脑脊液的结构）的不同热点区域的脂质积累；巨噬细胞/小胶质细胞的形成浸润脑实质；胶质细胞激活；激活 CP 和脑实质中的补体途径；巨噬细胞吞噬作用导致神经元轴突损失；血脑屏障（BBB）破坏； T/B 浆细胞聚集在脑膜和脑实质中。然而，这些变化是否是高脂血症的直接结果，还是由于 Apoe 的缺失，尚未确定。解决这些基本问题的一种方法是使用人源化转基因 Apoe 亚型特异性敲入小鼠。我们假设，在脑血流受损导致中风之前，高脂血症可能会诱发免疫介导的脑损伤。我们计划（目标1）通过使用老年人源化Apoe4敲入（KI）和Apoe3 KI小鼠来确定高脂血症和载脂蛋白E亚型在引起脑损伤中的作用； (目标 2) 分析补体抑制剂 C5 RNAi（肝脏特异性）对老年 Apoe-/- 小鼠的影响；并构建（Aim3）基于微阵列的转录图谱，并对老年Apoe-/-小鼠大脑进行FACS分析，以及体外生化载脂蛋白亚型结合和抑制研究，以及（Aim4）检测老年高脂血症性痴呆患者（非中风患者）脉络丛中的脂质和炎症细胞浸润。