APOE4 promotes pathogenesis in a mouse model of cancer chemotherapy-induced cognitive impairment

APOE4 促进癌症化疗引起的认知障碍小鼠模型的发病机制

• 批准号: 10561227
• 负责人: G WILLIAM REBECK
• 金额: $ 6.82万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561227
• 关键词: Acute; Adverse effects; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Anti-Inflammatory Agents; Antineoplastic Agents; Astrocytes; Attention; Autopsy; Behavior; Behavioral; Bexarotene; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Cell physiology; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Cognitive; Combination Drug Therapy; Controlled Study; Cyclophosphamide; DNA Damage; Data; Doxorubicin; Female; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genotype; Hour; Human; Impaired cognition; Impairment; Individual; Inflammation; Inherited; Intervention; Knock-in Mouse; Learning; Malignant Neoplasms; Measures; Memory; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurologic; Neurons; Paclitaxel; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Population; Pre-Clinical Model; Prevention; Prevention approach; Preventive treatment; Process; Reproducibility; Risk; Structure; Synapses; Tamoxifen; Testing; Time; Tissue Sample; Tissues; Translating; antagonist; base; behavioral impairment; cancer therapy; chemobrain; chemotherapeutic agent; chemotherapy; cognitive process; cohort; executive function; experimental study; exposed human population; genetic risk factor; hippocampal atrophy; human data; human tissue; in vivo; insight; learned behavior; male; mouse model; neurogenesis; novel; oxidative damage; pre-clinical; prevent; receptor for advanced glycation endproducts; risk variant; senescence; side effect; tau-1; therapeutic evaluation; tumor progression

Cancer chemotherapy causes marked cognitive impairment that involves deficits in learning & memory, attention, and executive functions. The best characterized genetic risk factor for chemotherapy induced cognitive impairment (CICI) is the E4 allele of APOE, which is also the strongest genetic risk factor for Alzheimer’s disease (AD). This commonality of risk provides a powerful opportunity to define mechanisms of the effects of APOE4 on cognitive dysfunction across conditions. We have developed a mouse model of APOE4-related CICI showing strong chemotherapy-induced cognitive effects in the APOE4 mice but not APOE3 mice, providing independent confirmation of this genetic risk in humans. We hypothesize that chemotherapy induces CNS damages related to APOE functions. We are testing specific mechanisms of APOE4-related vulnerability in four specific aims: Aim 1: Determine how chemotherapy affects pathogenic processes of Alzheimer’s disease. We will use a mouse model of amyloid influenced by the different APOE alleles (EFAD mice), to define mechanisms of chemotherapy on AD pathogenesis. We will expose cohorts of E3FAD and E4FAD mice to a chemotherapy regimen or vehicle control, and determine which AD pathological pathways are affected (A levels, phospho-tau, microglial and astrocytic activation, neuronal and synaptic loss, and hippocampal atrophy). Aim 2: Define mechanisms of APOE4-related chemotherapy sensitivity in a non-AD model. The APOE4 knock-in mouse model allows testing for CNS alterations that may underlie CICI in cognitively healthy individuals. We will test CNS mechanisms already identified in relation to the APOE4 genotype for exacerbation after chemotherapy, including: inflammation; neurogenesis; DNA damage; glial senescence; blood brain barrier breakdown; and oxidative damage. Aim 3: Identify specific chemotherapies associated with lower risks of cognitive impairment. We will use our sensitive and reproducible APOE4 mouse model to test whether some cancer chemotherapeutic approaches are safer than others. We will treat the susceptible APOE4 mice with four of the common cancer chemotherapies with different mechanisms of action. Aim 4: Test therapeutic approaches to prevention of chemotherapy-induced cognitive impairments. Identification of APOE-related mechanisms allows the targeted identification of preventative approaches. We initially will test an agent for increasing lipidated APOE levels (bexarotene), and an anti- inflammatory agent (an antagonist of the receptor for advance glycation endproducts (RAGE)). Together, these Aims will identify mechanisms underlying the risk of CICI in the large portion of the population carrying the APOE4 allele. In addition, the acute nature for the onset of CICI allows a more controlled approach for studying the negative effects of APOE4 in vivo, compared to only studying gradual processes of aging and neurodegeneration. Findings can be easily translated to clinical situations in terms of identifying at risk individuals and in terms of identifying new APOE4-related biomarkers of cognitive impairment.

癌症化学疗法会导致明显的认知障碍，涉及在学习和记忆中定义， 注意和执行功能。化学疗法的最佳特征遗传危险因素 认知障碍（CICI）是APOE的E4等位基因，这也是强大的遗传风险因素 阿尔茨海默氏病（AD）。这种风险的共同点为定义机制提供了有力的机会 APOE4对跨条件的认知功能障碍的影响。我们已经开发了一个鼠标模型 与APOE4相关的CICI在APOE4小鼠中表现出强烈的化学疗法诱导的认知作用，但没有 APOE3小鼠，为人类中这种遗传风险提供了独立的确认。我们假设这一点 化学疗法诱导与APOE功能有关的中枢神经系统损害。我们正在测试特定机制 四个特定目的中与APOE4相关的脆弱性：目标1：确定化学疗法如何影响致病性 阿尔茨海默氏病的过程。我们将使用受不同APOE影响的淀粉样蛋白的鼠标模型 等位基因（EFAD小鼠），以定义化学疗法在AD发病机理上的机制。我们将公开 E3FAD和E4FAD小鼠进行化疗方案或媒介物控制，并确定哪种AD病理 途径受到影响（A水平，磷酸-TAU，小胶质细胞和星形细胞激活，神经元和突触损失， 和海马萎缩）。 AIM 2：定义APOE4相关的化学疗法敏感性的机制 非AD模型。 APOE4敲入鼠标模型允许测试CNS改变，这可能是CICI的基础 在认知健康的个体中。我们将测试与APOE4相关的CNS机制 化学疗法后加重的基因型，包括：注射；神经发生； DNA损伤；神经胶质 感应；血脑屏障分解；和氧化损伤。目标3：确定特定的化学疗法 与较低的认知障碍风险有关。我们将使用敏感且可重现的APOE4 小鼠模型测试某些癌症化学治疗方法是否比其他方法更安全。我们将对待 具有四种常见癌症化学疗法的易感APOE4小鼠具有不同的机制 行动。目标4：预防化学疗法引起的认知的测试疗法方法 障碍。与APOE相关机制的识别允许对预防的目标识别 方法。最初，我们将测试脂化apoE水平（bexarotene）和抗 - 炎症剂（促进糖基化终产物的受体的拮抗剂（RAGE））。在一起，这些 目标将确定在携带大部分人口中CICI风险的基础机制 APOE4等位基因。此外，CICI发作的急性性质允许使用更受控的方法进行研究 与仅研究衰老的年级过程相比，apoE4在体内的负面影响 神经变性。从识别处于危险中的角度可以轻松地转化为临床情况 个人以及确定与APOE4相关的新生物标志物的认知障碍者。