Novel Strategies and Mechanisms to Target APOE and Alzheimer's Disease

描述（由申请人提供）：APOE基因型是迟发性阿尔茨海默病（AD）最强的遗传风险因素。ϵ4等位基因使AD发病风险增加3.7倍，2拷贝增加12倍；ϵ2等位基因可使风险降低约50%。证据有力地表明，这些影响的一个主要原因与载脂蛋白e蛋白与淀粉样蛋白- β (asβ)肽相互作用的能力有关，并以一种依赖于同型的方式影响asβ的清除和聚集。ApoE还可能通过影响突触/网络活动和脂质代谢等其他机制影响脑功能和功能障碍。目前尚不清楚如何针对载脂蛋白e生物学来制定治疗策略。我们的初步数据表明，当apoE4存在于脑间质液（ISF）中时，会减少asas清除并增强asas寡聚化/成纤维化，以及突触损伤。通过基因传递方法增加apoE2、E3和E4会减少、中性或增加asas聚集及其相关毒性。减少有毒apoE/ asβ复合物的数量可能是一种治疗方法。事实上，我们利用apoE单克隆抗体的初步数据显示，可能通过小胶质细胞介导的asas聚集体清除，asas病理减少和脑网络功能改善具有很强的作用。我们假设：1)通过增加大脑ISF中的apoE2水平，可能会降低asas聚集和毒性；2)用抗apoE抗体靶向apoE/ asas聚集体可能是一种潜在的治疗方法；3) ISF和突触中的apoE可能发挥重要的非ß相关功能，这对于理解基于apoE机制的任何治疗方法至关重要。具体目的是：1)确定改变脑内特定区室的apoE亚型水平是否会以亚型特异性和Aß依赖性的方式影响asas病理和相关的Aß依赖性脑功能障碍。2)探讨抗apoE抗体对表达人apoE亚型的人APP转基因（Tg）小鼠的影响及其作用机制。3)探讨apoE亚型对人apoE敲除小鼠、野生型和apoE敲除小鼠+/- asas突触结构/网络功能的潜在影响。

DESCRIPTION (provided by applicant): APOE genotype is by orders of magnitude the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The ϵ4 allele increases risk of AD by ~ 3.7 fold and 2 copies ~ 12 fold; the ϵ2 allele decreases risk by ~ 50%. Evidence strongly suggests that a major reason underlying these effects is related to the ability of the apoE protein to interact with the amyloid-ß (Aß) peptide and in an isoform-dependent fashion influence Aß clearance and aggregation. ApoE may also influence brain function and dysfunction via additional mechanisms such as influencing synaptic/network activity and lipid metabolism. It is not yet clear how to target apoE biology to develop therapeutic strategies. Our preliminary data suggest the hypothesis that apoE4, when present in the brain interstitial fluid (ISF), reduces Aß clearance and enhances Aß oligomerization/fibrillization, as well as synaptic damage. Increasing apoE2, E3, and E4 via gene delivery methods decreases, is neutral, or increases Aß aggregation and its associated toxicity. Decreasing the amount of toxic apoE/Aß complexes might serve as a therapeutic approach. In fact, our preliminary data utilizing monoclonal antibodies to apoE shows strong effects of decreasing Aß pathology and improving brain network function possibly via microglial-mediated clearance of Aß aggregates. We hypothesize that 1) decreasing Aß aggregation and toxicity may be possible by increasing apoE2 levels in the ISF of the brain; 2) targeting apoE/Aß aggregates with anti-apoE antibodies may serve as a potential therapeutic approach; and 3) that apoE in the ISF and at the synapse may play important non-Aß related functions, which will be critical to understand in the context of any therapeutics based on an apoE mechanism. The specific aims are: 1) To determine whether altering apoE isoform level in specific compartments in the brain influences Aß pathology and associated Aß-dependent brain dysfunction in an isoform-specific and Aß-dependent manner. 2) To explore the effects of anti-apoE antibodies and their mechanism of action in human APP transgenic (Tg) mice expressing human apoE isoforms. 3) To explore potential effects of apoE isoforms on synaptic structure/network function in human apoE knockin mice, wild-type, and apoE knockout mice +/- Aß.