课题基金 / 基金详情

Therapeutic targeting a membrane estrogen receptor with a novel non-steroidal compound for Alzheimer's disease

Therapeutic targeting a membrane estrogen receptor with a novel non-steroidal compound for Alzheimer's disease
使用新型非甾体化合物靶向膜雌激素受体治疗阿尔茨海默病
批准号:
10670490
负责人:
PHILIP F COPENHAVER
金额:
$76.69万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-15 至 2024-08-31
关键词:
AcuteAffectAgeAlzheimer associated neurodegenerationAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-42Amyloid beta-ProteinAnimal ModelAnimalsAutopsyBehavioral AssayBiological AssayBiological MarkersBlood - brain barrier anatomyBlood Coagulation FactorBrainBrain PathologyCellsCephalicCerebrospinal FluidChronicClinical TrialsCognitiveCoupledDementiaDiseaseElectrophysiology (science)EstradiolEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogen TherapyEstrogensEventFemaleFeminizationFormulationGlial Fibrillary Acidic ProteinGliosisGlutamatesGoalsHealthHippocampus (Brain)Hormone replacement therapyHormonesHumanImpaired cognitionImpairmentInterventionIschemiaLabelLaboratoriesLearningLigandsLightLinkLiverLong-Term PotentiationMalignant NeoplasmsMediatingMembraneMemoryMemory impairmentMenopauseMethodsMitochondriaModelingMonitorMusNerve DegenerationNeuronsOncogenicOralOutcomeOvarianPacemakersPathogenesisPathway interactionsPatientsPerimenopausePeripheralPharmaceutical PreparationsPhysiologyPlasmaPostmenopausePreparationPreventionPrimatesProductionProgestinsPropertyProtocols documentationPublishingReceptor SignalingRodentRoleSamplingSelective Estrogen Receptor ModulatorsSliceSteroidsSynapsesSynaptic TransmissionSystemTestingTherapeuticThrombosisTreatment ProtocolsVertebral columnWomanWorkabeta accumulationabeta oligomerabeta toxicityadverse outcomeage relatedalternative treatmentamyloid pathologybasecell typecognitive benefitscognitive functioncohortconfocal imagingcritical perioddementia riskdensityeffective therapyexcitotoxicityexperimental studyhyperphosphorylated tauin vivomalemouse modelmultiphoton imagingneurofilamentneuroinflammationneuron lossneuronal excitabilityneuropathologyneuroprotectionneurotoxicnovelolder womenpatch clamppre-clinical assessmentpreservationpreventprotective effectreproductive organresponsesexside effectsmall moleculesynaptic functiontargeted treatmenttau Proteinstau-1therapeutic targettherapeutically effectivethrombotictransmission processtreatment strategy

项目摘要

项目成果

PHILIP F COPENHAVER的其他基金

相似基金

相关文献

中文摘要
翻译
阿尔茨海默病(AD)的有效治疗方法仍然缺乏,而直接靶向β-淀粉样蛋白(Aβ)的药物仍然缺乏。
英文摘要
Effective treatments for Alzheimer's Disease (AD) are still lacking, and drugs that directly target β-amyloid (Aβ) and hyperphosphorylated Tau (pTau) have been largely unsuccessful. As an alternative, developing drugs that mitigate downstream neurodegenerative responses (independent of Aβ and pTau) might provide a more effective therapeutic strategy. Notably, the loss of ovarian steroid production significantly increases the risk of AD in postmenopausal women, raising hopes that hormone replacement could be used to prevent or treat AD. Unfortunately, clinical trials found that 17β-estradiol (E2) produced unacceptable side effects (including increased oncogenic and thrombotic events), and actually increased the risk of dementia in some patients. More recent trials targeting E2 to a perimenopausal `critical period' had better overall outcomes but still involved an increased risk for dementia. Likewise, selective estrogen receptor modulators (SERMs) targeting classical estrogen receptors are equally problematic, as chronic activation of either ERα or ERβ can still result in hormone-sensitive cancers. In contrast, STX is a novel SERM with unique properties. STX specifically engages GqMER (Gq-coupled membrane estrogen receptor), which has been shown to confer many of the neuroprotective benefits of E2 without its side effects. Oral STX readily crosses the blood-brain barrier and can be safely administered for sustained periods. Moreover, studies using both rodent and primate models of menopause have shown that STX treatment can rescue homeostatic functions as effectively as E2 without its side effects (including feminizing effects in males), reflecting the fact that GqMER is expressed by CNS neurons but not by other cell types in the brain or by peripheral reproductive organs. In cultured hippocampal neurons, STX was found to protect against the neurotoxic effects of both Aβ and pTau. Preliminary studies using the 5XFAD model of amyloid pathology indicate that oral STX can also protect against the loss of cognitive function, acting in part by supporting normal synaptic activity in the brain. Accordingly, we will use this well-characterized AD model to investigate the neuroprotective mechanism and functional benefits of STX in three complementary aims. Aim 1 will include a suite of behavioral assays (coupled with postmortem assays of neuropathology) to determine the beneficial effects of oral STX in protecting against AD-associated neurodegeneration. Aim 2 will employ electrophysiological protocols in hippocampal slice preparations to investigate the mechanisms by which STX mitigates the loss of synaptic functions that affect learning and memory in the AD brain. Aim 3 will use in vivo multiphoton imaging combined with subsequent confocal methods to analyze the neuroprotective effects of STX on mitochondrial function and synaptic spine integrity in the 5XFAD mice.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Macrophage-dependent regulation of neurotoxic APP fragments in a model system
A novel role for receptor tyrosine phosphatase in neuroblast migration
A novel role for receptor tyrosine phosphatase in neuroblast migration
Novel mechanisms of Ephrin-A reverse signaling in neuronal migration
海外基金