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/文摘