Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease

他克莫司在阿尔茨海默病犬模型中的临床前评价

• 批准号: 10446042
• 负责人: Elizabeth Head
• 金额: $ 408.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446042
• 关键词: 2 year old; 8 year old; APP-PS1; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Atrophic; Attenuated; Autopsy; Award; Biological Assay; Biological Markers; Blood; Blood Vessels; Brain; Brain Pathology; Calcineurin; Calcineurin inhibitor; Canis familiaris; Cells; Cerebrovascular Disorders; Chemicals; Clinical Trials; Cognition; Cognitive; Cognitive aging; Collection; Complementary therapies; Consumption; Control Groups; Data; Dementia; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Dose; Drug usage; Elderly; Exhibits; Experimental Models; FDA approved; FK506; Freezing; Functional disorder; Future; General Population; Genetic; Glial Fibrillary Acidic Protein; Graft Rejection; Health; Human; Hyperactivity; Image; Immune; Impaired cognition; Incidence; Inflammatory; Intervention; Kidney Transplantation; Label; Laboratories; Learning; Liquid substance; Literature; Longevity; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Measures; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Modification; Molecular; Molecular Target; Nerve Degeneration; Neurobiology; Neurons; Oral; Outcome; Outcome Measure; Pathology; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placebo Control; Placebos; Plant Roots; Plasma; Pre-Clinical Model; Predictive Analytics; Predisposition; Prevention; Property; Prophylactic treatment; Protein phosphatase; Proteomics; Publishing; Recovery; Rodent Model; Role; Sampling; Signal Transduction; Structure; Synapses; Tacrolimus; Testing; Transgenic Mice; Translating; Transplant Recipients; abeta deposition; allograft rejection; arterial spin labeling; beta amyloid pathology; biobehavior; brain health; brain size; calcineurin phosphatase; canine model; cerebrovascular; cerebrovascular imaging; cerebrovascular pathology; cognitive benefits; cognitive testing; design; druggable target; efficacy testing; epidemiology study; executive function; glial activation; human model; human old age (65+); improved; in vivo; memory recognition; metabolomics; middle age; mild cognitive impairment; mouse model; neurogenesis; neuroimaging; neuroinflammation; neuron loss; neuropathology; novel; object recognition; patient subsets; pre-clinical; preclinical evaluation; prevent; response; synaptic function; transcription factor; treatment strategy; white matter

Project Summary/Abstract Our proposed project is to test the hypothesis that calcineurin (CN) inhibition may be a promising intervention to prevent or slow Alzheimer disease (AD). The molecular target of our treatment strategy, CN, has emerged as a key mechanism related to AD pathophysiology. Signs of CN hyperactivity are found during early stages of cognitive decline in humans and in mouse models of AD. Studies across numerous laboratories, using a variety of experimental models, suggest that CN activity is both necessary and sufficient for the progression of key AD markers including Aβ deposition, neurodegeneration, neuroinflammation/glial activation, synapse dysfunction, and cognitive loss. To inhibit CN, we will use two treatments: 1) tacrolimus, an FDA-approved drug used for the prophylaxis of allograft rejection and a second line treatment for numerous immune/inflammatory disorders and; 2) Q134R, a novel hydroxyquinoline derivative that inhibits the CN-dependent transcription factor, NFAT (but does not inhibit CN activity). In rodent models, tacrolimus and Q134R exhibit anti-inflammatory and neuroprotective properties. Moreover, an epidemiological study found that the incidence of dementia was strikingly reduced in human kidney transplant patients administered tacrolimus, relative to age-matched subjects in the general population. We are using the preclinical canine model of human aging and AD. Beagles are metabolically similar to humans and spontaneously develop amyloid-β (Aβ) deposition and cognitive decline with advanced age. Further, the aging beagle shows predictive validity in regard to several high-profile anti-AD drug trials. In this project, we proposed to extend an ongoing longitudinal prevention study, initiated in middle aged 5-8 year old beagles that are being treated with tacrolimus, Q134R or placebo. At the age we initiated the intervention, most animals were cognitively intact and expected to have little or no brain Aβ. Dogs have been treated for 2.5 years and will complete 3 years of treatment prior to this new study where we propose to extend the treatment study to 5 years in total. One group of 15 dogs is being treated with tacrolimus (0.075 mg/kg/day, orally), a second group of 14 dogs is receiving Q134R (8 mg/day orally) and one group is serving as a placebo control group (n=14). Aim 1 will continue to assess multiple longitudinal cognitive outcomes including learning, executive function, spatial and object recognition memory. Aim 2 will expand on measures of plasma and CSF levels of AD biomarkers (e.g. NfL, Aβ, GFAP). Aim 3 will continue MRI measures of structure, and metabolic and vascular pathology to detect in vivo outcomes reflecting brain health. Aim 4 will focus on neuropathology (Aβ, glial activation, synapse dysfunction, neurodegeneration) and CN related pathway modifications. All outcome measures in this study are similar if not identical to those used in human clinical trials (including a human MR scanner, fluid biomarkers, assessment of analogous cognitive domains). We hypothesize that tacrolimus and Q134R will lead to maintenance of cognition, maintenance of CSF and plasma biomarker outcomes reflecting reduced brain pathology, maintenance of structural integrity, metabolic function and reduced vascular pathology and reduced AD neuropathology. These studies will provide a rigorous test of the CN hypothesis of AD and possibly pave the way for investigating if CN inhibition may serve as a primary or complementary treatment strategy in human AD clinical trials.

项目总结/摘要 我们提出的项目是检验钙调神经磷酸酶（CN）抑制可能是一种有希望的干预， 预防或减缓阿尔茨海默病（AD）。我们的治疗策略的分子靶点CN已经成为一种 与AD病理生理学相关的关键机制。CN活动过度的迹象是在早期阶段发现的 在人类和AD小鼠模型中的认知下降。许多实验室的研究，使用各种 的实验模型，表明CN活动是必要的，并充分的进展，关键AD 标记物包括Aβ沉积、神经变性、神经炎症/神经胶质活化、突触功能障碍， 和认知丧失为了抑制CN，我们将使用两种治疗方法：1）他克莫司，一种FDA批准的用于治疗CN的药物。 预防同种异体移植物排斥反应和多种免疫/炎性疾病的二线治疗; 2)Q134 R，一种新的羟基喹啉衍生物，可抑制CN依赖性转录因子NFAT（但 不抑制CN活性）。在啮齿动物模型中，他克莫司和Q134 R表现出抗炎和抗炎作用。 神经保护特性。此外，一项流行病学研究发现， 相对于年龄匹配的受试者，在给予他克莫司的人肾移植患者中显著降低 在普通人群中的比例。 我们正在使用人类衰老和AD的临床前犬模型。比格犬的新陈代谢与人类相似 并且随着年龄的增长自发地发展淀粉样蛋白-β（Aβ）沉积和认知能力下降。此夕h 老龄比格犬在几个高知名度的抗AD药物试验中显示出预测有效性。本课题 建议扩展一项正在进行的纵向预防研究，在中年5-8岁的比格犬中开始， 正在接受他克莫司、Q134 R或安慰剂治疗。在我们开始干预的年龄，大多数动物都 认知功能完好，预期大脑Aβ很少或没有。狗已经治疗了2.5年， 在这项新研究之前完成3年的治疗，我们建议将治疗研究延长至5年 总共一组15只狗用他克莫司（0.075 mg/kg/天，口服）治疗，第二组14只狗用他克莫司（0.075 mg/kg/天，口服）治疗， 狗接受Q134 R（8 mg/天口服），一组作为安慰剂对照组（n=14）。要求1 将继续评估多个纵向认知结果，包括学习，执行功能，空间 和物体识别记忆。目标2将扩展AD生物标志物的血浆和CSF水平的测量 (e.g. NfL、Aβ、GFAP）。目标3将继续MRI测量结构、代谢和血管病理， 检测反映大脑健康的体内结果。目的4将集中于神经病理学（Aβ、胶质细胞活化、突触 功能障碍、神经变性）和CN相关的途径修饰。本研究中的所有结局指标均为 与人类临床试验中使用的那些类似（如果不相同的话）（包括人类MR扫描仪，流体生物标志物， 类似认知域的评估）。我们假设他克莫司和Q134 R会导致 维持认知，维持CSF和血浆生物标志物结果，反映脑功能减退 病理学，维持结构完整性，代谢功能和减少血管病理学和减少 AD神经病理学这些研究将为AD的CN假设提供严格的检验，并可能为AD的研究铺平道路。 研究CN抑制是否可作为人类AD的主要或补充治疗策略的方法 临床试验