The Role of Viral Exposure and Age in Alzheimer's Disease Progression
病毒暴露和年龄在阿尔茨海默病进展中的作用
基本信息
- 批准号:10717223
- 负责人:
- 金额:$ 51.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAccelerationAddressAgeAge MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmericanAmyloid beta-ProteinAmyloid depositionApoptosisAutomobile DrivingBiological AssayBlood - brain barrier anatomyBlood VesselsCalciumCaregiversCell ReprogrammingCell SeparationCellsCerebrumCharacteristicsChronicClinicalClinical TrialsCognitiveConsensusCytomegalovirusCytomegalovirus InfectionsDataDependenceDevelopmentDisease ProgressionElderlyEpidemiologyEtiologyExposure toExtravasationFlow CytometryFrequenciesFunctional disorderGenetic RiskGenus HippocampusGlycolysisHerpesviridaeHumanImmunofluorescence ImmunologicImpaired cognitionIn VitroInbred BALB C MiceIndividualInfectionInflammationIronLifeLinkLysosomesMeasuresMediatingMediatorMetabolicMetabolic PathwayMetabolic dysfunctionMetabolismMitochondriaModelingMusNerve DegenerationNeurologic SymptomsNeuronsOnset of illnessOrganismOutcome StudyOutputOxidative PhosphorylationOxidative StressOxidative Stress InductionPECAM1 genePathologicPathway interactionsPatientsPeptidesPermeabilityPhenotypePopulationProtein AnalysisReportingRiskRisk FactorsRoleStressSuperoxidesSupporting CellTestingTight JunctionsTropismUbiquitinationViralViral Load resultVirusVirus DiseasesVoltage-Dependent Anion ChannelWestern BlottingWorkacute infectionaging brainblood-brain barrier permeabilizationbrain endothelial cellcognitive abilitycognitive functioncognitive testingcytochrome cdisease phenotypeemerging pathogenexperienceexperimental studyflexibilityhealthy agingimprovedinfection burdeninhibitormetabolic abnormality assessmentmetabolic phenotypemetabolic profilemild cognitive impairmentmitochondrial dysfunctionmitochondrial metabolismmouse modelneuron lossneuropathologynovel therapeutic interventionnovel therapeuticspathogenpathogen exposurepre-clinicalpreferencepreventprotein expressionrelease of sequestered calcium ion into cytoplasmsuccess
项目摘要
Currently afflicting more than 6.2 million Americans, Alzheimer’s Disease (AD) is a chronic neurodegenerative
condition that results from pathological brain aging and is the most common cause of cognitive dysfunction
among older adults. The lack of comprehensive understanding regarding drivers of AD initiation and progression
represents a critical barrier to progress for the field and has contributed to the current lack of viable treatment
options. Pathogens are emerging as a potential contributor to the etiology of AD. Neurological manifestations
and AD-associated phenotypes following acute infection with a variety of pathogens have been well documented.
The long-term consequences of repeated infection are inadequately studied, though emerging epidemiological
and preclinical evidence suggests that a higher lifetime infection burden impairs cognition, especially among
organisms carrying AD genetic risk. That pathogens impact cellular metabolism may represent a key AD-related
mechanism by which infection accelerates AD progression. What remains unknown is 1) whether a higher
lifetime exposure frequency to pathogens, especially those that have limited neuronal tropism, can promote an
AD phenotype, 2) how advanced age may potentiate this risk, and 3) the extent to which altered metabolism,
due to infection, contributes to these effects. Determination of how repeated viral exposure influences AD
neuropathological development and cognitive impairment as a function of age is a critical need for the field. Our
preliminary data demonstrates that intermittent infection induces altered metabolic phenotypes in brain
microvascular endothelial cells (BMVEC) and correlates with reduced cognitive function. We observe significant
decreases in markers associated with mitochondrial function in infected mice. We will leverage an aging murine
model with repeated exposure to viruses, to detect changes to metabolic pathways in the blood brain barrier and
how this correlates to cognitive ability. Aim 1 will address if repeated viral exposure accelerates age-associated
mitochondrial dysfunction of cells in the blood brain barrier, contributing to AD progression. Aim 2 will define how
voltage dependent anion channel 1 mechanistically alters mitochondrial function in BMVEC with age. Aim 3,
defines how viruses impacts blood brain barrier permeability as a function of age, accelerating AD progression.
The outcome of these studies will contribute crucial understanding of how pathogen exposure influences AD
progression and cognitive function. This project could potentially revealing novel therapeutic or preventative
targets to prevent AD progression, offering hope to millions of patients and their caregivers.
阿尔茨海默病(AD)是一种慢性神经退行性疾病,目前折磨着超过620万美国人
项目成果
期刊论文数量(0)
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Kevin John Zwezdaryk其他文献
Kevin John Zwezdaryk的其他文献
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{{ truncateString('Kevin John Zwezdaryk', 18)}}的其他基金
The role of the CMV-associated reactive oxygen species in age-related
CMV 相关活性氧在年龄相关性中的作用
- 批准号:
10318555 - 财政年份:2020
- 资助金额:
$ 51.94万 - 项目类别:
The role of the CMV-associated reactive oxygen species in age-related
CMV 相关活性氧在年龄相关性中的作用
- 批准号:
10313478 - 财政年份:2020
- 资助金额:
$ 51.94万 - 项目类别:
The role of the CMV-associated reactive oxygen species in age-related
CMV 相关活性氧在年龄相关性中的作用
- 批准号:
10402506 - 财政年份:2012
- 资助金额:
$ 51.94万 - 项目类别:
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