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.

癌症化疗会导致明显的认知障碍，包括学习和记忆方面的缺陷， 注意力和执行功能。化疗诱发的最具特征性的遗传危险因素 认知障碍(CiCi)是载脂蛋白E的E4等位基因，也是高脂血症的最大遗传危险因素。 阿尔茨海默病(AD)。风险的这种共性提供了一个强大的机会来定义 载脂蛋白4对各种条件下认知功能障碍的影响。我们已经开发了一种小鼠模型 载脂蛋白E4相关的CiCi在APOE4小鼠中表现出强烈的化疗诱导的认知效应，但不是 APOE3小鼠，提供了对人类这种遗传风险的独立确认。我们假设 化疗引起与载脂蛋白E功能相关的中枢神经系统损害。我们正在测试特定的机制， 四个特定目标中的载脂蛋白E4相关脆弱性：目标1：确定化疗如何影响致病因素 阿尔茨海默病的发展过程。我们将使用受不同载脂蛋白影响的淀粉样蛋白的小鼠模型 等位基因(EFAD小鼠)，以明确化疗在AD发病机制中的作用。我们将揭露一批 E3FAD和E4FAD小鼠以化疗方案或赋形剂为对照，并确定AD的病理类型 通路受到影响(A水平，磷酸化tau，小胶质细胞和星形胶质细胞激活，神经元和突触丢失， 和海马区萎缩)。目的2：明确APOE4相关化疗敏感性的机制。 非AD模型。APOE4敲入小鼠模型允许测试可能作为CiCi基础的中枢神经系统改变 在认知健康的个体中。我们将测试已经确定的与APOE4相关的中枢神经系统机制 化疗后加重的基因类型包括：炎症；神经发生；DNA损伤；神经胶质细胞 衰老；血脑屏障破坏；以及氧化损伤。目标3：确定特定的化疗方法 与较低的认知障碍风险相关。我们将使用我们敏感且可重现的APOE4 用小鼠模型测试某些癌症化疗方法是否比其他方法更安全。我们会请客的 易感的APOE4小鼠使用四种不同机制的常见癌症化疗药物 行动。目的4：测试预防化疗所致认知障碍的治疗方法 减损。APOE相关机制的确定允许有针对性地确定预防性 接近了。我们最初将测试一种提高脂化APOE水平的试剂(贝沙罗汀)，以及一种抗 炎症剂(高级糖基化终末产物受体(RAGE)的拮抗剂)。加在一起，这些 AIMS将在很大一部分携带CII的人群中确定潜在的CCI风险机制 载脂蛋白E4等位基因。此外，CiCi发病的急性性为研究提供了一种更可控的方法。 APOE4在体内的负面影响，与只研究逐渐老化的过程和 神经退行性变。在识别风险方面，这些发现可以很容易地转化为临床情况 在识别认知障碍的新的APOE4相关生物标记物方面。