APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease

APOE 等位基因转换作为阿尔茨海默病的治疗方法

• 批准号: 10589257
• 负责人: Lance Allen Johnson
• 金额: $ 64.24万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589257
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Apolipoprotein E; Astrocytes; Automobile Driving; Biological; Birth; Brain; Candidate Disease Gene; Cells; Cerebrovascular Disorders; Cerebrum; Clinical Trials; Cognitive deficits; Cre lox recombination system; Data; Development; Elderly; Functional disorder; Future; Gene Expression Profile; Genes; Genetic; Genetic Recombination; Genotype; Homozygote; Human; Hyperlipidemia; Image; Immune; Impaired cognition; Individual; Inflammation; Knockout Mice; Late Onset Alzheimer Disease; Length; Link; Longevity; Measures; Metabolic; Metabolism; Modeling; Mouse Strains; Mus; Myelin; Nature; Nerve Degeneration; Neurons; Odds Ratio; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Phagocytosis; Physiological; Play; Pre-Clinical Model; Risk; Role; Series; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Supplementation; Synapses; Testing; Therapeutic; amyloid pathology; apolipoprotein E-4; brain dysfunction; cell type; cerebrovascular; efficacy testing; gene therapy; genetic risk factor; in vivo; induced pluripotent stem cell; interest; lipidomics; loss of function; metabolomics; mouse model; neuroinflammation; neuropathology; novel; overexpression; protective effect; stable isotope; tau Proteins; transcriptomics

Abstract In comparison to the highly protective E2 allele of Apolipoprotein E (APOE), the E4 allele has been associated with a host of detrimental effects, including, but not limited to, increased amyloid deposition, more severe tau pathology, heightened neuroinflammation, cerebrovascular dysfunction, and various metabolic deficits. With its strong risk profile and varied biological mechanisms, APOE itself has emerged as an attractive candidate for gene therapy. In addition to providing a much-needed preclinical model for ongoing and future trials, exploration of E4 to E2 allele ‘switching’ has the potential to help answer several fundamental and longstanding biological questions in the field. For example, which ApoE-synthesizing cell-type(s) drive AD pathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associated deficits set in stone at birth (developmentally), or is later-life APOE editing a feasible approach to mitigate AD neuropathology and cognitive dysfunction? To this end, we have generated a series of novel APOE ‘switch’ (4s2) mouse models that allow for temporal and cell-specific allele switching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full- length human ApoE4 at baseline, and importantly, when crossed to various inducible CreERT2 strains, the switch successfully leads to efficient recombination and expression of human ApoE2 in cell types of interest. Given the remarkable protective effects of E2 carriage and the various roles of ApoE at differing steps of AD pathogenesis, we hypothesize that astrocyte-specific allelic switching to E2 will simultaneously rescue multiple metabolic, immune, and neuropathological deficits associated with E4. We propose to leverage these unique mouse models to determine the therapeutic window for CNS-specific E4 to E2 allele switching to simultaneously mitigate metabolic deficits, neuroinflammation, cerebrovascular dysfunction, amyloid pathology, and cognitive dysfunction. If successful, this proposal will provide an essential preclinical model for ongoing and future clinical trials, and will provide critical new information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic ApoE modulation.

摘要 与载脂蛋白E（APOE）的高度保护性E2等位基因相比，E4等位基因具有 与一系列有害影响有关，包括但不限于， 淀粉样蛋白沉积，更严重的tau病理，神经炎症加剧，脑血管 以及各种代谢缺陷。由于其强烈的风险特征和各种生物学特性， 在基因治疗机制方面，APOE本身已经成为一种有吸引力的基因治疗候选者。此外 为正在进行的和未来的试验提供急需的临床前模型，探索E4， E2等位基因“转换”有可能帮助回答一些基本和长期存在的问题。 生物学领域的问题。例如，哪种ApoE合成细胞类型驱动AD E4携带者的发病机制，哪些对E2携带者最有保护作用？与E4相关 缺陷在出生时（发育上）就固定下来了，或者晚年APOE编辑是一种可行的方法 减轻AD神经病理学和认知功能障碍为此，我们制定了一个 一系列新的APOE“开关”（4s 2）小鼠模型，允许时间和细胞特异性等位基因 从E4切换到E2。我们的初步数据证实这些4s 2小鼠合成了一个完整的- 重要的是，当与各种诱导型CreERT 2杂交时， 菌株中，该开关成功地导致了人ApoE 2的有效重组和表达 感兴趣的细胞类型。考虑到E2载体的显著保护作用和各种 ApoE在AD发病机制的不同阶段的作用，我们假设星形胶质细胞特异性 等位基因转换为E2将同时拯救多种代谢、免疫和 与E4相关的神经病理学缺陷。我们建议利用这些独特的鼠标 模型，以确定CNS特异性E4至E2等位基因转换的治疗窗口， 同时减轻代谢缺陷、神经炎症、脑血管功能障碍 淀粉样病变和认知功能障碍如果成功的话，这一提议将提供一个 为正在进行的和未来的临床试验提供重要的临床前模型，并将提供关键的新的 关于理想的细胞、区域和时间特异性治疗机会的信息 ApoE调节。