Cerebrovascular contributions to APOE4-mediated brain bioenergetic deficits in Alzheimer's disease
脑血管对 APOE4 介导的阿尔茨海默病脑生物能缺陷的影响
基本信息
- 批准号:10739352
- 负责人:
- 金额:$ 44.95万
- 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:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Acetyl-CoA CarboxylaseAgeAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinAnimalsApolipoprotein EBioenergeticsBiological MarkersBrainCellsCerebrovascular DisordersCerebrovascular systemChemicalsDiseaseEnergy SupplyEquilibriumExhibitsFailureFatty AcidsFunctional disorderGene SilencingGenotypeGlucoseHumanImpairmentIndividualInflammationKetone BodiesKetonesLate Onset Alzheimer DiseaseLevocarnitineLinkLipidsMediatingMetabolismMitochondriaMolecularMusMutationNeurofibrillary TanglesNeuronsNutrientOxidative StressPathogenesisPathologyPathway interactionsPericytesPersonsPlayProcessProtein IsoformsResearchRiskRoleSenile PlaquesSmooth Muscle MyocytesStable Isotope LabelingSystemTestingTherapeuticTimeWorkacylcarnitineage relatedaging brainapolipoprotein E-4brain endothelial cellbrain parenchymaburden of illnesscell agecerebrovascularcerebrovascular pathologyexperiencefatty acid metabolismfatty acid oxidationfatty acid transportflexibilitygenetic risk factorglucose metabolismglucose transportglucose uptakehyperphosphorylated tauimprovedin vivoinhibitorinsightlipid metabolismlong chain fatty acidmouse modelneuroinflammationnoveloxidationpre-clinicalsynaptic functiontau Proteins
项目摘要
The apolipoprotein E (APOE) E4 allele is one of the major genetic risk factors for late-onset
Alzheimer’s disease (AD) and an important contributor to cerebrovascular (CV) dysfunction,
which is now considered a major component of AD pathology. Recent advances in AD research
suggest that E4 carriers have an age-dependent vulnerability in supplying glucose to the brain,
which corresponds with lower glucose metabolism and precedes brain amyloid and tau
pathologies. The CV system regulates glucose transport to the brain to support neuronal
bioenergetics. With age, individuals with the E4 allele experience deficits in their ability to
transport nutrients to the brain, which eventually, forces neurons to perform fatty acid (FA)
metabolism. Fatty acid metabolism is harmful if performed in neurons as it can contribute to
oxidative stress. The process of FA metabolism requires L-carnitine for transporting FA as
acylcarnitines (CAR) into mitochondria (L-carnitine bioenergetics). The importance of this
system in AD is highlighted by our recent study showing that L-carnitine-bioenergetic deficits are
present in E4 carriers and correlate with CV pathologies in AD. Our animal studies herein show
pathways that link glucose sensing with acetyl-CoA carboxylase (ACC) for L-carnitine-
bioenergetics are altered in the cerebrovasculature of mice with targeted replacement of mouse
APOE with human APOE4 (E4-TR) and AD mouse models with the human APOE4 isoform.
We, therefore, hypothesize that E4 disrupts L-carnitine-bioenergetics within the CV cells, which
corresponds with impaired transport of nutrients to the brain parenchyma. This increases the
reliance on L-carnitine-bioenergetics within neurons and contributes to oxidative stress and
inflammation in the brain. To test this hypothesis, we will first determine whether brain
endothelial cells (BEC) or mural cells experience altered L-carnitine bioenergetics and
determine the differential impact of APOE genotypes within both cells with age. We will then
determine if boosting L-carnitine bioenergetics pathways by inhibiting ACC in BEC will help
restore nutrient balance in the brain parenchyma. The proposed studies will provide novel
insights into the role of ACC-mediated L-carnitine bioenergetics for developing therapeutic
strategies specifically targeting E4 carriers, who experience a significantly higher
cerebrovascular disease burden associated with AD pathogenesis.
载脂蛋白E (APOE) E4等位基因是迟发性糖尿病的主要遗传危险因素之一
项目成果
期刊论文数量(0)
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Laila Abdullah其他文献
Laila Abdullah的其他文献
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{{ truncateString('Laila Abdullah', 18)}}的其他基金
The role of adaptive immunity in organophosphate induced CNS injury
适应性免疫在有机磷诱导的中枢神经系统损伤中的作用
- 批准号:
10629511 - 财政年份:2023
- 资助金额:
$ 44.95万 - 项目类别:
The effects of APOE4 on carnitine/acylcarnitine mediated bioenergetic deficits in Alzheimer's disease
APOE4 对肉碱/酰基肉碱介导的阿尔茨海默病生物能缺陷的影响
- 批准号:
10370296 - 财政年份:2021
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$ 44.95万 - 项目类别:
Long term assessment of neurological effects after red tide exposure
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10155490 - 财政年份:2020
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$ 44.95万 - 项目类别:
Influence of APOE genotypes on blood brain barrier transport of DHA by mfsd2a in Alzheimer's Disease
APOE基因型对阿尔茨海默病中mfsd2a血脑屏障转运DHA的影响
- 批准号:
10292958 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Identifying APOE related lipid biomarkers for diagnosing chronic neurocognitive deficits in TBI patients
鉴定用于诊断 TBI 患者慢性神经认知缺陷的 APOE 相关脂质生物标志物
- 批准号:
10454875 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Influence of APOE genotypes on blood brain barrier transport of DHA by mfsd2a in Alzheimer's Disease
APOE基因型对阿尔茨海默病中mfsd2a血脑屏障转运DHA的影响
- 批准号:
9663028 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Influence of APOE genotypes on blood brain barrier transport of DHA by mfsd2a in Alzheimer's Disease
APOE基因型对阿尔茨海默病中mfsd2a血脑屏障转运DHA的影响
- 批准号:
10515657 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Identifying APOE related lipid biomarkers for diagnosing chronic neurocognitive deficits in TBI patients
鉴定用于诊断 TBI 患者慢性神经认知缺陷的 APOE 相关脂质生物标志物
- 批准号:
9910069 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Identifying APOE related lipid biomarkers for diagnosing chronic neurocognitive deficits in TBI patients
鉴定用于诊断 TBI 患者慢性神经认知缺陷的 APOE 相关脂质生物标志物
- 批准号:
10614552 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
Influence of APOE genotypes on blood brain barrier transport of DHA by mfsd2a in Alzheimer's Disease
APOE基因型对阿尔茨海默病中mfsd2a血脑屏障转运DHA的影响
- 批准号:
10043826 - 财政年份:2019
- 资助金额:
$ 44.95万 - 项目类别:
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