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: 10198086
• 负责人: Elizabeth Head
• 金额: $ 38.25万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198086
• 关键词: 7 year old; 9 year old; Adverse effects; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Alzheimer' 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

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 阿尔茨海默病（AD）的抑制策略。比格犬的新陈代谢与人类相似，并且自发地 随着年龄的增长，β-淀粉样蛋白 (Aβ) 会沉积。因此，老化的比格犬模型表明 在几项备受瞩目的抗 AD 药物试验中具有出色的预测有效性。我们的分子靶点 治疗策略 CN 最近已成为 AD 病理生理学的关键机制。 CN 的标志 在人类和 AD 小鼠模型中，在认知能力下降的早期阶段就发现了多动症。研究 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。抑制CN， 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 治疗多种免疫/炎症性疾病。在动物模型中，他克莫司表现出有效的抗 具有抗炎、神经保护、或许还有延长寿命的特性。此外，最近的流行病学 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。 在这个项目中，5-6 个月大的比格犬将接受为期 1 年的行为/认知筛查。 6-7点 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 与认知状态相匹配。一组将连续接受他克莫司（0.075mg/kg/天，口服）治疗 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） 治疗期。目标 2 将使用 MRI/MRS 测量脑灌注、脑 新陈代谢和结构完整性。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） 死后脑组织。这些研究将为 AD 的 CN 假说提供严格的检验，并可能 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。

项目成果

Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.

他克莫司可防止比格犬大脑中与年龄相关的微观结构变化。

• DOI: 10.1523/jneurosci.0361-21.2021
• 发表时间: 2021
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Radhakrishnan,Hamsanandini;Ubele,MargoF;Krumholz,StephanieM;Boaz,Kathy;Mefford,JenniferL;Jones,ErinDenhart;Meacham,Beverly;Smiley,Jeffrey;Puskás,LászlóG;Powell,DavidK;Norris,ChristopherM;Stark,CraigEL;Head,Elizabeth
• 通讯作者: Head,Elizabeth