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

基本信息

批准号：
10188365
负责人：
Elizabeth Head
金额：
$ 31.39万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188365
关键词：
7 year old 9 year old Adverse effects Age Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Amyloid deposition Animal Model Animals Anti-Inflammatory Agents Atrophic Attenuated Autopsy Behavioral Biochemical Biological Assay Biological Markers Blood Brain Calcineurin Calcineurin inhibitor Canis familiaris Cerebrospinal Fluid Cerebrovascular Disorders Cerebrum Clinical Trials Cognition Cognitive Dementia Development Diffusion Magnetic Resonance Imaging Disease Dose Elderly Exhibits Experimental Models FDA approved FK506 Freezing Functional disorder General Population Genes Genetic Gold Human Hyperactivity Image Immune Immunohistochemistry Impaired cognition Incidence Individual Inflammatory Investigation Kidney Transplantation Label Laboratories Liquid substance Literature Longevity Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maintenance Matched Group Measures Metabolic Metabolic dysfunction Metabolism Modeling Molecular Molecular Target Mus Nerve Degeneration Neurons Oral Oral Administration Organ Transplantation PPP3CA gene Pathologic Pathology Pathway interactions Perfusion Pharmaceutical Preparations Pharmacology Pharmacotherapy Placebos Plant Roots Pre-Clinical Model Preclinical Testing Predisposition Property Prophylactic treatment Protein phosphatase Proteolysis Recovery Rodent Role Safety Sampling Signal Transduction Solid Spin Labels Standard Model Structure Synapses Tacrolimus Testing Time Transgenic Mice Transgenic Organisms Translations Transplant Recipients Work abeta deposition allograft rejection amyloid pathology biobehavior brain metabolism brain tissue calcineurin phosphatase cell type cerebrovascular cerebrovascular imaging cerebrovascular pathology cognitive function cytokine druggable target epidemiology study familial Alzheimer disease glial activation improved middle age mouse model mutant neurogenesis neuroimaging neuroinflammation neuron loss neuropathology neurotoxicity overexpression preclinical evaluation prevent relating to nervous system screening synaptic function therapy design treatment duration treatment strategy white matter

项目摘要

7. Project Summary/Abstract This project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN) inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneously develop amyloid-β (Aβ) deposition with advanced age. Consequently, the aging beagle model has shown exceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of our treatment strategy, CN, has recently emerged as a key mechanism for 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 biobehavioral markers including Aβ deposition, neurodegeneration, neuroinflammation/glial activation, synapse dysfunction, and cognitive loss. To inhibit CN, we will use tacrolimus, an FDA-approved drug for the prophylaxis of allograft rejection and a second line treatment for numerous immune/inflammatory disorders. In animal models, tacrolimus exhibits potent anti- inflammatory, neuroprotective, and perhaps lifespan extending properties. Moreover, a recent epidemiological study found that the incidence of dementia was strikingly reduced in human kidney transplant patients taking tacrolimus, relative to age-matched subjects in the general population. In this project, 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7 months-of age (prior to the development of significant amyloid pathology), dogs will be sorted into two groups matched for cognitive status. One group will received tacrolimus (.075mg/kg/day, orally) continuously for the next two years, while the other group will receive placebo. Aim 1 will assess multidomain cognition and measure blood and CSF biomarkers (e.g. Aβ and cytokines) at multiple time points across the tacrolimus treatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion, brain metabolism, and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assays to assess AD biomarkers (e.g. Aβ deposition, glial activation, synapse loss, and neurodegeneration) and CN- related signaling parameters (e.g. cell-type specific expression, CN proteolysis, and NFAT activation) in postmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possibly pave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human AD clinical trials.

7. 项目总结/摘要该项目使用老化的比格犬和纵向治疗设计来测试钙调神经磷酸酶 (CN) 的潜力比格犬的新陈代谢与人类相似，并且是自发的。老化比格犬模型显示，随着年龄的增长，β-淀粉样蛋白 (Aβ) 会沉积。在多项备受瞩目的抗 AD 药物试验中具有出色的预测有效性。治疗策略 CN 最近已成为 AD 病理生理学的关键机制。在人类和 AD 小鼠模型的认知衰退早期阶段发现了多动症。许多实验室使用各种实验模型表明 CN 活性既对于关键 AD 生物行为标志物（包括 Aβ 沉积）的进展是必要和充分的，神经退行性变、神经炎症/神经胶质激活、突触功能障碍和认知丧失。我们将使用他克莫司，这是 FDA 批准的用于预防同种异体移植排斥的药物和二线药物在动物模型中，他克莫司可治疗多种免疫/炎症性疾病。此外，最近的流行病学研究还发现，它具有抗炎、神经保护和延长寿命的作用。研究发现，人类肾移植患者服用药物后，痴呆症的发病率显着降低他克莫司，相对于一般人群中年龄匹配的受试者。在该项目中，5-6 个月大的比格犬将在 6-7 岁时接受为期 1 年的行为/认知筛查。几个月大时（在出现明显的淀粉样蛋白病理之前），狗将被分为两组一组将连续接受他克莫司（0.075mg/kg/天，口服）。未来两年，另一组将接受安慰剂，目标 1 将评估多领域认知和在他克莫司的多个时间点测量血液和脑脊液生物标志物（例如 Aβ 和细胞因子）目标 2 将使用 MRI/MRS 测量脑灌注、大脑的纵向变化。目标 3 将使用免疫组织化学和各种生化检测。评估 AD 生物标志物（例如 Aβ 沉积、神经胶质激活、突触丢失和神经变性）和 CN- 相关信号参数（例如细胞类型特异性表达、CN 蛋白水解和 NFAT 激活）这些研究将为 AD 的 CN 假说提供严格的检验。为研究 CN 抑制在人类 AD 中作为主要或补充治疗策略铺平道路临床试验。