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

描述（申请人提供）：APOE基因型是晚发性阿尔茨海默病（AD）最强的遗传风险因素。等位基因104使AD的风险增加约3.7倍，2个拷贝增加约12倍;等位基因102使风险降低约50%。有证据有力地表明，这些作用的主要原因与apoE蛋白与淀粉样蛋白-β（A β）肽相互作用并以同种型依赖性方式影响A β清除和聚集的能力有关。ApoE还可以通过其他机制影响脑功能和功能障碍，例如影响突触/网络活动和脂质代谢。目前尚不清楚如何靶向apoE生物学来开发治疗策略。我们的初步数据表明，假设apoE 4，当存在于脑间质液（ISF），减少Ablation清除，并增强Ablation寡聚化/flipidization，以及突触损伤。通过基因递送方法增加apoE 2、E3和E4降低、中性或增加ApoE 2聚集及其相关毒性。减少毒性apoE/ApoE复合物的量可能是一种治疗方法。事实上，我们利用针对apoE的单克隆抗体的初步数据显示，可能通过小胶质细胞介导的ApoE聚集体的清除，降低ApoE病理学和改善脑网络功能的强烈作用。我们推测：1）通过增加脑ISF中apoE 2的水平可能降低ApoE聚集和毒性; 2）用抗apoE抗体靶向apoE/ApoE聚集体可能作为一种潜在的治疗方法; apoE在ISF和突触中可能发挥重要的非ApoE相关功能，这对于理解基于apoE机制的任何治疗方法都是至关重要的。具体目标是：1）确定改变脑中特定区室中的apoE同种型水平是否以同种型特异性和ApoE依赖性方式影响ApoE病理学和相关的ApoE依赖性脑功能障碍。2)目的探讨抗apoE抗体对表达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基因敲入小鼠、野生型和apoE基因敲除小鼠+/-ApoE中突触结构/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.