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.

项目摘要/摘要 我们提出的项目是检验钙调神经酶（CN）抑制作用的假设，可能是对 预防或减慢阿尔茨海默氏病（AD）。我们治疗策略的分子靶标CN已成为一个 与AD病理生理学有关的关键机制。在早期的早期阶段发现了CN多动症的迹象 人类和AD小鼠模型的认知能力下降。使用多种多样的众多实验室的研究 在实验模型中，表明CN活性对于钥匙AD的进展既需要又足够 包括Aβ沉积，神经变性，神经炎症/神经胶质激活，突触功能障碍，包括标记， 和认知损失。为了抑制CN，我们将使用两种治疗方法：1）他克莫司，一种由FDA批准的药物 对多种免疫/炎症性疾病的预防预防和第二线治疗； 2）Q134R，一种新型羟喹啉衍生物，抑制CN依赖性转录因子NFAT（但是 不抑制CN活性）。在啮齿动物模型中，他克莫司和Q134R暴露了抗炎和 神经保护特性。此外，一项流行病学研究发现，痴呆症的发生是 相对于年龄匹配的受试者，在人类肾移植患者中大幅降低了他的克莫司 在一般人群中。 我们正在使用人类衰老和AD的临床前犬模型。猎犬在代谢上与人类相似 并随着年龄的增长，赞助发展淀粉样蛋白-β（Aβ）的沉积和认知下降。此外， 衰老的小猎犬在几项备受瞩目的抗AD药物试验方面显示出预测性的有效性。在这个项目中，我们 建议扩展一项正在进行的预防纵向预防研究，该研究是在中年5-8岁的小猎犬中发起的 正在用他克莫司，Q134R或安慰剂治疗。在我们开始干预的年龄，大多数动物是 认知完整，预计很少或没有脑Aβ。狗已经接受了2。5年的治疗 在这项新研究之前完成3年的治疗，我们建议将治疗研究扩展到5年 总共。一组15只狗正在克莫司（0.075 mg/kg/day，口服），第二组14组 狗正在接受Q134R（口服8 mg/天），一组作为安慰剂对照组（n = 14）。目标1 将继续评估多个纵向认知结果，包括学习，执行功能，空间 和对象识别内存。 AIM 2将扩展血浆和CSF水平的AD生物标志物的测量值 （例如NFL，Aβ，GFAP）。 AIM 3将继续对结构以及代谢和血管病理的MRI测量 检测反映大脑健康的体内结果。 AIM 4将专注于神经病理学（Aβ，神经胶质激活，突触 功能障碍，神经变性）和与CN相关的途径修改。这项研究的所有结果措施是 与人类临床试验中使用的类似（包括人类MR扫描仪，流体生物标志物， 评估类似认知领域）。我们假设他克莫司和Q134R将导致 维持认知，维持CSF和等离子体生物标志物结果，反映了大脑减少 病理学，结构完整性的维持，代谢功能和减少的血管病理和减少 AD神经病理学。这些研究将对AD的CN假设进行严格的测试，并可能铺平 调查CN抑制是否可以作为人类AD的主要或完整治疗策略的方法 临床试验。