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: 10334558
• 负责人: G WILLIAM REBECK
• 金额: $ 38.69万
• 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/10334558
• 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，包括学习和记忆的缺陷， 注意力和执行功能。化疗诱导的最佳遗传风险因素 认知障碍（CICI）是APOE的E4等位基因，也是最强的遗传风险因素， 阿尔茨海默病（AD）。风险的这种共性为确定风险的机制提供了一个强有力的机会。 APOE 4对不同条件下认知功能障碍的影响。我们已经建立了一个小鼠模型， APOE 4相关CICI在APOE 4小鼠中显示出强烈的化疗诱导的认知效应， APOE 3小鼠，为人类的这种遗传风险提供了独立的确认。我们假设 化疗诱导与APOE功能相关的CNS损伤。我们正在测试 APOE 4相关的脆弱性在四个具体目标：目标1：确定化疗如何影响致病性 老年痴呆症的过程。我们将使用一种受不同APOE影响的淀粉样蛋白小鼠模型， 等位基因（EFAD小鼠），以确定化疗对AD发病机制的机制。我们将揭露 E3 FAD和E4 FAD小鼠进行化疗方案或溶媒对照，并确定其中AD病理 通路受到影响（A β水平，磷酸化tau，小胶质细胞和星形胶质细胞活化，神经元和突触损失， 和海马萎缩）。目的2：明确APOE 4相关化疗敏感性的机制， 非AD模型APOE 4基因敲入小鼠模型允许测试可能是CICI基础的CNS改变 在认知健康的个体中。我们将测试已经确定的与APOE 4相关的CNS机制。 化疗后恶化的基因型，包括：炎症;神经发生; DNA损伤;神经胶质 衰老;血脑屏障破坏;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相关。我们将使用我们敏感和可重复的APOE 4 小鼠模型来测试某些癌症化疗方法是否比其他方法更安全。本公司对待 易感的APOE 4小鼠与四种常见的癌症化疗具有不同的机制， 行动上目的4：测试预防化疗诱导的认知障碍的治疗方法 损伤APOE相关机制的鉴定允许有针对性地鉴定预防性 接近。我们最初将测试一种增加脂化APOE水平的药物（贝沙罗汀）和一种抗- 炎症剂（晚期糖基化终产物受体（AGEs）的拮抗剂）。所有这些 目的是确定大部分携带CICI的人群中CICI风险的潜在机制， APOE 4等位基因。此外，CICI发病的急性性质允许采用更受控的研究方法 APOE 4在体内的负面影响，与只研究逐渐老化的过程相比， 神经变性在识别风险方面，研究结果可以很容易地转化为临床情况 个体和识别新的APOE 4相关的认知障碍生物标志物。