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

针对 APOE 和阿尔茨海默病的新策略和机制

基本信息

批准号：
8779836
负责人：
DAVID M. HOLTZMAN
金额：
$ 59.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8779836
关键词：
Accounting Adult Age-associated memory impairment Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Animal Model Antibodies ApoE knockout mouse Apolipoprotein E Behavior Biology Brain Cerebral Amyloid Angiopathy Complex Data Disease Functional disorder Gene Delivery Genetic Genotype Health Human Image Intercellular Fluid Knowledge Laboratories Late Onset Alzheimer Disease Lead Link Mediating Metabolism Methods Microglia Microscopy Monoclonal Antibodies Morphology Nerve Degeneration Neurobiology Optics Pathogenesis Pathology Peptides Play Prevention Process Protein Isoforms Proteins Public Health Publishing Relative (related person)Risk Risk Factors Role Signal Transduction Structure Synapses Techniques Testing Therapeutic Toxic effect Transgenic Mice Viral Vector Wild Type Mouse Work apolipoprotein E-3 apolipoprotein E-4 base cell type genetic risk factor improved in vivo lipid metabolism novel novel strategies prevent response synaptic function tomography treatment effect

项目摘要

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.

描述（由申请人提供）：APOE 基因型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 风险增加约 3.7 倍，而 ϵ2 等位基因则增加 2 倍约 12 倍；证据强烈表明，这些影响的主要原因与 apoE 蛋白与淀粉样蛋白-ß 相互作用的能力有关。 (Aß) 肽并以异构体依赖性方式影响 ApoE 清除和聚集，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大脑功能和功能障碍。我们的初步数据表明，apoE4 存在于脑间质液 (ISF) 中时，会降低 Aß 清除率并增强 Aß 寡聚化/纤维化，如通过基因传递方法增加 apoE2、E3 和 E4 会减少、中性或增加 Aß 聚集及其相关毒性。事实上，我们的方法可能是一种治疗方法。利用 apoE 单克隆抗体的初步数据表明，可能通过小胶质细胞介导的 Aß 聚集物清除来减少 Aß 病理并改善大脑网络功能。 1) 通过增加大脑 ISF 中的 apoE2 水平可以减少 Aß 聚集和毒性；2) 使用抗 apoE 抗体靶向 apoE/Aß 聚集体可能作为一种潜在的治疗方法；突触处的 ApoE 可能发挥重要的非 Aß 相关功能，这对于理解任何基于 apoE 机制的治疗至关重要。确定改变大脑特定区室中的 apoE 同工型水平是否会以同工型特异性和 Aß 依赖性方式影响 Aß 病理学和相关的 Aß 依赖性脑功能障碍 2) 探索抗 apoE 抗体的作用及其作用机制。表达人 apoE 亚型的人 APP 转基因 (Tg) 小鼠 3) 探讨 apoE 亚型对人 apoE 敲入中突触结构/网络功能的潜在影响。小鼠、野生型和 apoE 敲除小鼠 +/- Aß。