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

• 批准号: 9060227
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 55.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/9060227
• 关键词: Accounting; Adult; Age-associated memory impairment; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Animal Model; Antibodies; ApoE knockout mouse; Apolipoprotein E; Array tomography; Behavior; Biology; Brain; Cerebral Amyloid Angiopathy; Complex; Data; Disease; Functional disorder; Gene Delivery; Genetic; Genotype; Health; Human; Image; Intercellular Fluid; Knock-in Mouse; 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; Risk; Risk Factors; Role; Signal Transduction; Structure; Synapses; Techniques; Testing; Therapeutic; Toxic effect; Transgenic Mice; Viral Vector; Work; apolipoprotein E-3; apolipoprotein E-4; base; brain dysfunction; cell type; genetic risk factor; improved; in vivo; lipid metabolism; novel; novel strategies; prevent; response; synaptic function; treatment effect

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（由适用提供）：APOE基因型按数量级的阶数命令，即晚期发病的阿尔茨海默氏病（AD）的强遗传风险因素。 ϵ4等位基因将AD的风险增加〜3.7倍和2份〜12倍； ϵ2等位基因将风险降低约50％。证据强烈表明，这些作用的主要原因与ApoE蛋白与淀粉样蛋白（Aß）胡椒相互作用的能力以及同工型依赖性时尚影响Aß清除率和聚集有关。 APOE还可以通过影响突触/网络活性和脂质代谢等其他机制来影响大脑功能和功能障碍。尚不清楚如何靶向APOE生物学来制定理论策略。我们的初步数据表明，当APOE4存在于大脑室间液（ISF）中时，降低了Aß清除率并增强了Aß低聚/纤颤，实际上，我们的初步数据利用单克隆抗体来促进单克隆抗体来降低了脑力学和脑网络的强大效果，从而可以通过微糖进行促进型的促进型促进。我们假设1）通过增加大脑ISF的APOE2水平来减少Aß聚集和毒性； 2）用抗APOE抗体靶向APOE/Aß聚集体可能是一种潜在的治疗方法； 3）ISF和突触中的APOE可能起重要的非Aß相关功能，这对于基于APOE机制的任何治疗的背景下将是至关重要的。具体目的是：1）确定大脑中特定隔室的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抗体的作用及其在表达人apoE同工型的人类应用转基因（TG）小鼠中的作用机理。 3）探索APOE同工型对人ApoE敲除小鼠，野生型和APOE基因敲除小鼠+/-aß中突触结构/网络功能的潜在影响。