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

描述(由申请人提供)：APOE基因是晚发性阿尔茨海默病(AD)的最强遗传风险因素。ϵ4等位基因使AD发病风险增加3.7%，ϵ2等位基因使AD发病风险降低50%。有力的证据表明，这些效应背后的一个主要原因与apoE蛋白与淀粉样蛋白(A？)肽相互作用的能力有关，并以异构体依赖的方式影响A？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额外机制影响大脑功能和功能障碍。目前尚不清楚如何针对载脂蛋白E生物学制定治疗策略。我们的初步数据表明，假设当apoE4存在于脑间质液(ISF)中时，会减少A？清除，增强A？寡聚/纤化，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A？聚集及其相关毒性。减少毒性载脂蛋白E/A？复合体的数量可能是一种治疗方法。事实上，我们利用抗apoE单抗的初步数据显示，可能通过小胶质细胞介导的清除A？聚集体，可以减轻A？病理和改善脑网络功能的强烈效果。我们假设，1)通过增加脑内ISF中APOE2的水平，可以减少A？聚集和毒性；2)用抗apoE抗体靶向apoE/A？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A？相关功能，这对于在任何基于apoE机制的治疗的背景下理解这一点将是至关重要的。其具体目的是：1)确定改变大脑中特定隔区的apoE亚型水平是否会以一种同型特异性和Aü依赖的方式影响A？病理和相关的A？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基因敲除小鼠、野生型和apoE基因敲除小鼠突触结构/网络功能的影响。

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.