Modulation of TNFα as a Treatment for Alzheimer's Disease and Related Dementia
Modulation of TNFα as a Treatment for Alzheimer's Disease and Related Dementia
批准号:
10511026
负责人:
Gareth R Howell
金额:
$46.93万
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:
2022-08-20 至 2024-07-31
关键词:
AblationAdultAffectAgeAge-associated memory impairmentAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAmyloid beta-ProteinAnimal ModelApolipoprotein EApoptoticAreaBindingBiochemicalBloodBlood CirculationBlood VesselsBlood flowBody CompositionBrainCause of DeathCellsCerebrovascular CirculationCerebrovascular DisordersCerebrovascular systemCerebrumClinicalClinical TrialsDataDeath DomainDementiaDevelopmentDiabetes MellitusDoseDown-RegulationElderlyEnvironmental Risk FactorEvaluationFosteringFunctional disorderFundingFutureGeneticGenotypeGlucose TransporterGrantHealthHumanIRS1 geneImmune signalingImpaired cognitionImpairmentIndividualInflammatoryInsulinInsulin ReceptorInsulin ResistanceInsulin-Dependent Diabetes MellitusInterventionLate Onset Alzheimer DiseaseLinkMeasuresMediatingMembraneMetabolicMetabolic dysfunctionMetabolismMethodologyModelingMolecularMolecular AnalysisMouse StrainsMusNOS3 geneNeurodegenerative DisordersNon-Insulin-Dependent Diabetes MellitusPET/CT scanPathologyPathway interactionsPerfusionPersonsPharmacologic SubstancePharmacologyPhenotypePhysiologyPopulationPreventionProductionProtein Binding DomainProtein-Serine-Threonine KinasesReceptor SignalingRegulationReportingResearchRiskRoleSenile PlaquesSignal PathwaySignal TransductionSignaling MoleculeStrokeSubgroupSuperoxidesTNF geneTNFRSF1A geneTNFRSF1B geneTRADD geneTamoxifenTestingTissuesUnited States National Institutes of HealthVariantVascular DementiaVascular DiseasesWorkX-Ray Computed Tomographyadvanced dementiaage relatedagedaging populationbasecerebrovascularcerebrovascular healthcerebrovascular pathologycohortcomorbiditycytokinedesensitizationendophenotypegenetic risk factorglucose metabolismglucose transporthypoperfusionimprovedinhibitormouse modelneuroprotectionneurovascularnovelpatient populationpharmacokinetics and pharmacodynamicspreservationpreventreceptorrecruitrestorationtissue regenerationtooltumor ablation
中文摘要
标题:调节TNFα作为阿尔茨海默病和相关痴呆的治疗
英文摘要
TITLE: Modulation of TNFα as a Treatment for Alzheimer’s Disease and Related Dementia
ABSTRACT
Growing evidence suggest a major determinant of age-related cognitive impairment, and associated dementia,
is cerebral insulin dependent diabetes and vascular health. While Alzheimer’s disease (AD) is the most common
form of dementia, and is characterized by amyloid plaques and TAU pathology, clinical trials targeting these
pathologies have not been successful. Studies show AD cases are comorbid with diabetes and cerebrovascular
pathology. Under normal physiology, insulin mediates glucose transport into the cell via the glucose transporter;
however, in pathophysiological conditions, the insulin receptor signal becomes desensitized, resulting in
metabolic dysfunction. Comorbid with these changes are cerebrovascular pathologies, which manifest as
reduced blood flow, strokes, and micro-infarcts. Despite these observations, few clinical trials have studied brain
insulin dependent hypometabolism and associated vascular dysfunction. We, and others, believe that metabolic
and vascular dysregulation can be considered initiators of a spectrum of dementias that share common pathways
of activation. Improving or preserving metabolism and cerebrovascular health through aging may reduce risk or
prevent cognitive impairment and dementia. We hypothesize that modulating the Tumor Necrosis Factor
alpha (TNFα) pathway will preserve cerebral metabolism and maintain vascular and health. The TNFα
pathway is a key regulator in immune signaling, which has been shown to increase with age. Moreover, recent
studies have shown that TNFα mediated action via the TNFα receptors (TNFR1 and TNFR2) is implicated in the
glycolytic and vascular dysregulation observed with advancing age and dementia. Previous work in our lab has
identified that mice carrying APOEE4/E4 show uncoupling of perfusion and glucose metabolism with age, similar
to the phenotype also reported in the human patient population. Therefore, this grant will use mice carrying
APOEE4/E4, and we will modulate TNFα signaling through two different approaches. In Aim 1, we will determine
whether the APOEE3/E4 variant show similar neurovascular dysfunction as APOEE4/E4, as this is more common in
the human population. If so, we will utilize this for all subsequent aims. We will then use timed ablation of TNFα
through the use of a newly developed B6.TNFαflox/flox mouse paired with a tamoxifen inducible cre, CAGGCre-
ER (JAX stock #004682) to determine if global genetic TNFα ablation leads to preservation of cerebrovascular
function. This will be assessed using highly translational clinical measure such as PET/CT. Blood and tissue will
be collected for biochemical and molecular analyses. In Aim 2, we will take a complementary interventional
approach using R-7050 as a tool compound to elucidate the role of TNFR1 signaling in metabolic and vascular
dysfunction by disrupting TNFR1-TRADD-RIP1 signal transduction. Combined these data will lay the groundwork
for exploring the molecular mechanisms of TNFα signal in metabolic and vascular dysfunction in AD and related
dementias.
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