Profiling Pathologically Normal ApoE Variants to Identify Pathways for AD

描述(由申请人提供)：该项目旨在探索为什么载脂蛋白E(ApoE4)的E4变异体的遗传是AD发病和进展的重要风险因素。提出这一建议的理由是基于下列几点观察：1)相对于ApoE3的遗传，ApoE4变体的遗传是AD的一个非常强大的风险因素；2)ApoE4个体在生命早期，即在斑块和缠结出现之前几十年，就已经出现明显的脑部形态和功能改变的表现；以及3)ApoE4的遗传是多种疾病的风险因素，表明影响神经保护、修复、细胞存活等的通路普遍存在缺陷。我们的第二个推测是，虽然ApoE4通过其对清除的影响而影响淀粉样β蛋白(A2)的积累，但还有一些由ApoE受体家族信号介导的途径也可能提供第二个易损点。观察表明，ApoE4的遗传是涉及脑损伤的其他疾病或事件的风险因素，而且ApoE4个体神经元形态的变化表明，对损伤做出有利反应的能力较弱。对侮辱的整体反应不佳，再加上严重依赖载脂蛋白E介导的通路的细胞类型的选择性脆弱性，可以解释为什么载脂蛋白E4变异的遗传比其他神经退行性疾病更是AD的问题。该项目旨在确定具有不同载脂蛋白E变体的人类和小鼠模型中的风险途径。我们预计，这些研究将在这个庞大的人群中产生关于AD病因学的新想法，可能会提出新的预防或治疗措施。 公共卫生相关性：载脂蛋白E4携带者患AD的风险显著增加，但临床试验正变得越来越分层，以排除载脂蛋白E4携带者。由于有可能在生命的早期就进行载脂蛋白E基因的检测，因此确定增加风险的途径是非常必要的，因为从早期开始进行治疗干预是可能的。从病理正常的载脂蛋白E4携带者中分析脆弱细胞群体的RNA有望识别新的风险途径，从而允许生物标记物和治疗开发。在ApoE靶标小鼠上进行相同的实验将提供相关数据，并产生关于这一重要AD风险因素的有价值的小鼠模型的新信息。

DESCRIPTION (provided by applicant): The project aims to explore why inheritance of the E4 variant of apolipoprotein E (ApoE4) is a significant risk factor for onset and progression of AD. The rationale for this proposal is driven by several observations: 1) that inheritance of the ApoE4 variant is a very strong risk factor for AD relative to inheritance of ApoE3, 2) that manifestations of altered brain morphology and function are apparent in ApoE4 individuals, early in life, decades before plaques and tangles are apparent, and 3) that inheritance of ApoE4 is a risk factor for several diseases suggesting a general deficit in pathways affecting neuroprotection, repair, cell survival etc. We anticipate that altered pathways impacted by ApoE of relevance to AD can be identified by a comparison of gene profiles between vulnerable cell populations of ApoE variants. Our second speculation is that while it is clear that ApoE4 affects the accumulation of amyloid-beta (A2) due to its effects on clearance, there are pathways mediated by ApoE receptor family signaling that could also provide a secondary point of vulnerability. This is demonstrated by the observation that inheritance of ApoE4 is a risk factor for other diseases or events that involve brain injury, and that the altered morphology of neurons of ApoE4 individuals suggests less capacity to respond favorably to injury. The combination of a poor overall response to insult, coupled with selective vulnerability of cell types that rely heavily on ApoE mediated pathways could explain why inheritance of ApoE4 variant is more of a problem for AD than other neurodegenerative diseases. The project aims to identify pathways at risk in both humans and a mouse model with different ApoE variants. We anticipate that these studies will generate new ideas about the etiology of AD in this large population group that might suggest novel preventative or therapeutic measures. PUBLIC HEALTH RELEVANCE: ApoE4 carriers are at significantly heightened risk of AD but clinical trials are becoming increasingly stratified to exclude ApoE4 carriers. As it is possible to test for ApoE genotype very early in life, it is imperative to identify pathways that increase risk as it may be possible to intervene therapeutically from an early age. RNA profiling vulnerable cell populations from pathologically normal ApoE4 carriers is expected to identify novel pathways at risk, allowing for biomarker and therapeutic developments. Performing identical experiments on ApoE targeted mice will provide corrolatory data, as well as generating novel information on this valuable mouse model of an important AD risk factor.