Targeting carbonic anhydrases in Alzheimer's disease
靶向碳酸酐酶治疗阿尔茨海默病
基本信息
- 批准号:10602459
- 负责人:
- 金额:$ 45.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAD transgenic miceAcetazolamideAgeAge MonthsAgingAltitudeAltitude SicknessAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapyAmyloidAmyloid beta-ProteinAmyloidosisAnimal ModelBehavioralBicarbonatesBiochemicalBlood VesselsBrainCASP3 geneCarbon DioxideCarbonic Anhydrase IICarbonic Anhydrase InhibitorsCaspaseCell DeathCell Death InductionCell modelCellsCellular StressCerebral Amyloid AngiopathyCerebral EdemaCerebrumCessation of lifeChronicClinicalClinical TrialsDataDementiaDepositionDevelopmentDiseaseDoseDrug usageEndothelial CellsEndotheliumEnergy-Generating ResourcesEnzymesEventExhibitsFDA approvedFailureFamilyFunctional disorderFutureGlaucomaGoalsHumanHydrogen PeroxideImmunohistochemistryImpaired cognitionIn VitroLearningLinkMediatingMembrane PotentialsMemoryMemory impairmentMethazolamideMitochondriaModelingMusNerve DegenerationNeurofibrillary TanglesNeurogliaNeuronsPathologicPathologyPathway interactionsPharmacological TreatmentPhosphorylationPredispositionPreventionProductionProtonsReactive Oxygen SpeciesReportingResearchRespirationSeizuresSenile PlaquesSynapsesTauopathiesTestingTherapeuticTimeToxic effectTransgenic MiceTransgenic ModelTranslatinganalogbehavioral phenotypingbrain cellcarbonate dehydratasecerebral amyloidosiscognitive functioncytochrome cdrug repurposingexperimental studyin vivomitochondrial dysfunctionmitochondrial membranemouse modelneurofibrillary tangle formationneuropathologyneurovascularnovelnovel therapeuticspreservationpreventprotective effecttau Proteins
项目摘要
Project Summary
Mitochondria are considered one of the early targets in Alzheimer’s disease (AD). Preserving mitochondrial
function can be a key strategy to prevent energetic failure in the AD brain and to inhibit the production of
reactive oxygen species (ROS) and activation of caspases, thereby reducing neuronal, glial and vascular cell
dysfunction and death, and hindering the progression of AD pathology. Our previous studies and others
demonstrated that amyloid beta (Aβ) causes brain cell death through mitochondrial dysfunction and release of
cytochrome C (CytC). Our preliminary data revealed that methazolamide (MTZ) and acetazolamide (ATZ), two
carbonic anhydrase inhibitors (CAIs) highly active on mitochondrial carbonic anhydrases (CAs) are able to
prevent mitochondrial dysfunction and CytC release in brain vascular and neuronal cells and in animal models
of cerebral amyloidosis, through the inhibition of mitochondrial H2O2 production and mitochondrial
depolarization. CAIs such as MTZ and ATZ are currently FDA approved for glaucoma, high altitude sickness,
seizures, and other clinical indications. Previous studies reported increases in CAs expression in the aging and
AD brain, confirming the relevance of CAs as a novel and previously unexplored target for AD therapy.
We hypothesize that CA inhibition prevents mitochondrial dysfunction and cell death mechanisms
induced by both Aβ and tau in vitro and in vivo, ameliorating neurovascular pathology and cognitive
impairment in AD models. In Aim 1, we will perform a pharmacological treatment with the CAIs in a
transgenic mouse model presenting both amyloidosis and tauopathy. We will feed 3xTg-AD transgenic
mice with the two CAIs. We will start treating mice prior to onset of pathology (from 6 months of age), and
when pathology is already present (from 11 months of age). Mitochondrial function, ROS production, caspase
activation, cell death, amyloid and tau deposition will be evaluated in the mouse brain biochemically and by
immunohistochemistry. Cognitive function will be evaluated behaviorally. In Aim 2, we will assess in vitro the
efficacy of CAIs for prevention of tau-mediated mitochondrial dysfunction, using human neuronal, glial
and endothelial cells in culture challenged with phosphorylated (pathological) tau species. In Aim 3, we will
validate mitochondrial carbonic anhydrases as important targets associated to AD pathology and
susceptible to modulation by amyloid and tau challenge. We will assess expression levels and specific
localization of CA-VA, -VB and -II in age-matched AD and healthy human brains. We will silence mitochondrial
CAs in endothelial, glial and neuronal cells to test the hypothesis that CA silencing will prevent mitochondrial
dysfunction pathways and cell death induced by Aβ and tau pathologic species similarly to CA inhibition.
Goal of the proposed line of research is to validate CAs as a target for amyloidosis and tauopathy and translate
this study to a clinical trial to repurpose CAIs for AD and other dementias in the close future.
项目总结
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)
专利数量(0)
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Silvia Fossati其他文献
Silvia Fossati的其他文献
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{{ truncateString('Silvia Fossati', 18)}}的其他基金
Vascular MicroRNA-212 in CAA and Alzheimer's disease
CAA 和阿尔茨海默病中的血管 MicroRNA-212
- 批准号:
10807420 - 财政年份:2023
- 资助金额:
$ 45.23万 - 项目类别:
Targeting carbonic anhydrases in Alzheimer's disease
靶向碳酸酐酶治疗阿尔茨海默病
- 批准号:
10374878 - 财政年份:2019
- 资助金额:
$ 45.23万 - 项目类别:
Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors
心血管危险因素增强 CAA 介导的内皮功能障碍
- 批准号:
10017325 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors
心血管危险因素增强 CAA 介导的内皮功能障碍
- 批准号:
10427355 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors
心血管危险因素增强 CAA 介导的内皮功能障碍
- 批准号:
10183346 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors
心血管危险因素增强 CAA 介导的内皮功能障碍
- 批准号:
10166202 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
Leveraging biomarkers for personalized treatment of alcohol use disorder comorbid with PTSD
利用生物标志物对合并 PTSD 的酒精使用障碍进行个性化治疗
- 批准号:
10473677 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
Leveraging biomarkers for personalized treatment of alcohol use disorder comorbid with PTSD
利用生物标志物对合并 PTSD 的酒精使用障碍进行个性化治疗
- 批准号:
10237283 - 财政年份:2018
- 资助金额:
$ 45.23万 - 项目类别:
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