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:10446042
- 负责人:
- 金额:$ 408.35万
- 依托单位:
- 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 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:2 year old8 year oldAPP-PS1AgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer’s disease biomarkerAmyloidAmyloid beta-ProteinAnimalsAnti-Inflammatory AgentsAtrophicAttenuatedAutopsyAwardBiological AssayBiological MarkersBloodBlood VesselsBrainBrain PathologyCalcineurinCalcineurin inhibitorCanis familiarisCellsCerebrovascular DisordersChemicalsClinical TrialsCognitionCognitiveCognitive agingCollectionComplementary therapiesConsumptionControl GroupsDataDementiaDiffusion Magnetic Resonance ImagingDiseaseDisease MarkerDoseDrug usageElderlyExhibitsExperimental ModelsFDA approvedFK506FreezingFunctional disorderFutureGeneral PopulationGeneticGlial Fibrillary Acidic ProteinGraft RejectionHealthHumanHyperactivityImageImmuneImpaired cognitionIncidenceInflammatoryInterventionKidney TransplantationLabelLaboratoriesLearningLiquid substanceLiteratureLongevityMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMaintenanceMeasuresMetabolicMetabolic dysfunctionMetabolismModelingModificationMolecularMolecular TargetNerve DegenerationNeurobiologyNeuronsOralOutcomeOutcome MeasurePathologyPathway interactionsPeripheralPersonsPharmaceutical PreparationsPharmacologyPharmacotherapyPlacebo ControlPlacebosPlant RootsPlasmaPre-Clinical ModelPredictive AnalyticsPredispositionPreventionPropertyProphylactic treatmentProtein phosphataseProteomicsPublishingRecoveryRodent ModelRoleSamplingSignal TransductionStructureSynapsesTacrolimusTestingTransgenic MiceTranslatingTransplant Recipientsabeta depositionallograft rejectionarterial spin labelingbeta amyloid pathologybiobehaviorbrain healthbrain sizecalcineurin phosphatasecanine modelcerebrovascularcerebrovascular imagingcerebrovascular pathologycognitive benefitscognitive testingdesigndruggable targetefficacy testingepidemiology studyexecutive functionglial activationhuman modelhuman old age (65+)improvedin vivomemory recognitionmetabolomicsmiddle agemild cognitive impairmentmouse modelneurogenesisneuroimagingneuroinflammationneuron lossneuropathologynovelobject recognitionpatient subsetspre-clinicalpreclinical evaluationpreventresponsesynaptic functiontranscription factortreatment strategywhite matter
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Elizabeth Head其他文献
Elizabeth Head的其他文献
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{{ truncateString('Elizabeth Head', 18)}}的其他基金
T21RS Meeting June 2022 Long Beach, California
T21RS 会议 2022 年 6 月 加利福尼亚州长滩
- 批准号:
10469127 - 财政年份:2022
- 资助金额:
$ 408.35万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 408.35万 - 项目类别:
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