Influence of APOE genotype on cerebrovascular cell pathobiology in AD, and the contribution of microglia inflammation
APOE基因型对AD脑血管细胞病理学的影响以及小胶质细胞炎症的贡献
基本信息
- 批准号:10289340
- 负责人:
- 金额:$ 16.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidAmyloid beta-ProteinApolipoprotein EAutomobile DrivingAutopsyBlood - brain barrier anatomyBlood VesselsBlood flowBrainCellsCerebral Amyloid AngiopathyCerebral small vessel diseaseCerebrovascular CirculationCerebrovascular systemCerebrumClinicalClinical TrialsCognitiveDementiaDepositionDiseaseEndothelial CellsEtiologyEventFutureGenerationsGenesGenetic TranscriptionGenotypeGoalsHealthHemorrhageHumanHuman PathologyImpairmentInflammationKnock-in MouseLeptomeningesLesionLongitudinal StudiesMapsMediatingMicrogliaModelingMolecularMusNerve DegenerationNeurofibrillary TanglesNeurogliaNeurologicNeurologic DysfunctionsNeuronal DysfunctionNeuronsNewborn InfantOutcomePathogenesisPathogenicityPathologyPatientsPerfusionPericytesPhenotypePlayPopulationProtein IsoformsProteomicsRecurrenceReportingResearchResearch DesignRiskRisk FactorsRoleSenile PlaquesSmooth Muscle MyocytesSymptomsSystemTechniquesTherapeuticTimeTimeLineTissuesToxic effectTranscriptValidationVascular DiseasesVascular Smooth MuscleWorkage related neurodegenerationaging brainamyloid pathologyapolipoprotein E-4arteriolebasecerebrovascularcerebrovascular healthcerebrovascular lesioncognitive functiondifferential expressionhealthy aginghemodynamicshuman modelmind controlmouse modelmutantneurovascularnovelnovel therapeutic interventionnovel therapeuticsphase III trialpre-clinicalprodromal Alzheimer&aposs diseaseresponserestorationtau Proteinstherapeutic targettranscriptomics
项目摘要
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the predominant type of
dementia, marked by brain deposits of amyloid plaques and neurofibrillary tangles. An often overlooked
pathognomonic lesion of AD is cerebrovascular degeneration. Abnormalities in cerebral blood flow are a
preclinical feature of AD that manifest many years before symptom onset. Vascular lesions are also routinely
observed in AD brains at different stages of the disease. Disruptions to cerebrovascular integrity can impact on
neuronal function, however, the main driver of these vascular changes in AD remains elusive.
The Apolipoprotein E4 (APOE4) allele is one of the strongest risk factors for AD, and has been shown to
significantly impact on cerebrovascular health, precipitating deficits in cerebral perfusion, vascular lesions and
damage to the blood brain barrier. Yet, more longitudinal studies are needed to better understand how APOE4
can significantly impact on cerebrovascular cell pathobiology in the sequelae of AD pathogenesis.
In the brain, APOE is produced primarily by glial cells, and in AD, disease associated microglia (DAM’s)
are known to upregulate APOE expression, which mediates the transcriptional proinflammatory phenotype of
these cells. DAM’s have been shown to drive the outcome and pace of APOE-mediated neuronal dysfunction,
but very little is currently known about the role they play in contributing to cerebrovascular changes in AD,
particularly, how this is influenced by APOE genotype.
To address these questions, we plan to use mouse models expressing human forms of APOE and A𝛽 to
clarify the role played by APOE4 as a molecular driver of cerebrovascular cell pathobiology, and how this is
influenced by DAM’s. We will explore longitudinal cerebrovascular cell pathobiology at timepoints
representing pre, peri and post onset of
A
𝛽 pathology using histopathological and ultrastructural analyses. We
will also confirm the contribution of DAMs on cerebrovascular pathobiology by utilizing microglia ablation
techniques to depopulate DAMs and also repopulate newborn microglia in our mouse models. To date, no
studies have characterized the molecular transcripts of reactive cerebrovascular cell phenotypes in these
combined models. Thus, we will conclude our studies using single cell gene analyses of cerebrovascular cells
(endothelial cells, pericytes, smooth muscle cells) to reveal their unique and detailed time-course of responses.
We will confirm differentially expressed genes in autopsied cerebrovascular tissue from staged AD cases to
validate the translational relevance of our findings and map against mouse AD-related pathogenic timelines.
From this proposal, we aim to identify novel (cerebrovascular) cell specific targets in the early stages of
disease through which the APOE4 allele confers neurological risk. Our future goal will be to explore the
functional effects of these targets, and to provide new therapeutic opportunities to promote cerebrovascular
health and restoration of cognitive function in AD.
阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病,并且是阿尔茨海默病的主要类型。
痴呆,以大脑淀粉样斑块和神经纤维缠结的沉积为特征。一个经常被忽视
AD的特征性病变是脑血管变性。脑血流量异常是一种
AD的临床前特征是在症状发作前多年表现出来的。血管病变也是常规的
在AD的不同阶段的大脑中观察到。脑血管完整性的破坏可能会影响
然而,神经元功能,AD中这些血管变化的主要驱动力仍然难以捉摸。
载脂蛋白E4(APOE4)等位基因是AD最强的危险因素之一,并已被证明
显著影响脑血管健康,导致脑灌注不足、血管病变和
对血脑屏障的损害。然而,需要更多的纵向研究来更好地了解APOE4如何影响人类的健康。
可显著影响AD发病后遗症脑血管细胞病理生物学。
在大脑中,APOE主要由神经胶质细胞产生,而在AD中,则由疾病相关小胶质细胞(DAM)产生。
已知可上调APOE表达,而APOE介导转录促炎表型,
这些细胞。DAM已被证明驱动APOE介导的神经元功能障碍的结果和速度,
但目前对它们在AD脑血管变化中的作用知之甚少,
特别是,这如何受到APOE基因型的影响。
为了解决这些问题,我们计划使用表达人类形式的APOE和Aβ的小鼠模型,
阐明APOE4作为脑血管细胞病理学的分子驱动因素所发挥的作用,以及这是如何
受到DAM的影响。我们将探讨纵向脑血管细胞病理生物学在时间点
分别代表发病前、发病后和发病后
一
使用组织病理学和超微结构分析进行组织病理学检查。我们
还将通过利用小胶质细胞消融来证实DAM对脑血管病理生物学的贡献
技术来减少DAM的数量,并在我们的小鼠模型中重新填充新生的小胶质细胞。至今没有
研究已经表征了这些脑血管病患者中反应性脑血管细胞表型的分子转录物,
组合模型。因此,我们将使用脑血管细胞的单细胞基因分析来结束我们的研究
(内皮细胞、周细胞、平滑肌细胞)以揭示其独特且详细的反应时间过程。
我们将确认AD分期病例尸检脑血管组织中差异表达的基因,
验证我们的研究结果的翻译相关性,并绘制小鼠AD相关致病时间表。
从这个建议,我们的目标是确定新的(脑血管)细胞特异性目标的早期阶段,
APOE4等位基因赋予神经风险的疾病。我们未来的目标是探索
这些目标的功能效应,并提供新的治疗机会,以促进脑血管疾病
健康和恢复AD认知功能。
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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Joseph O Ojo其他文献
Joseph O Ojo的其他文献
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{{ truncateString('Joseph O Ojo', 18)}}的其他基金
The role of PPARγ in astrocyte pathobiology after exposure to repetitive mild traumatic brain injury
PPARγ 在重复性轻度脑外伤后星形胶质细胞病理学中的作用
- 批准号:
10739968 - 财政年份:2023
- 资助金额:
$ 16.2万 - 项目类别:
THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI
PTEN 在反复轻度 TBI 暴露后微胶质病理学中的作用
- 批准号:
10511758 - 财政年份:2022
- 资助金额:
$ 16.2万 - 项目类别:
The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury
重复性轻度创伤性脑损伤后 PPARγ 在小胶质细胞病理学中的作用
- 批准号:
10557217 - 财政年份:2022
- 资助金额:
$ 16.2万 - 项目类别:
THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI
PTEN 在反复轻度 TBI 暴露后微胶质病理学中的作用
- 批准号:
10683340 - 财政年份:2022
- 资助金额:
$ 16.2万 - 项目类别:
The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury
重复性轻度创伤性脑损伤后 PPARγ 在小胶质细胞病理学中的作用
- 批准号:
10355038 - 财政年份:2022
- 资助金额:
$ 16.2万 - 项目类别:
Influence of APOE4 genotype on microglial pathobiology and tau pathology after repetitive mTBI
APOE4 基因型对重复 mTBI 后小胶质细胞病理学和 tau 病理学的影响
- 批准号:
10575479 - 财政年份:2022
- 资助金额:
$ 16.2万 - 项目类别:
Influence of APOE genotype on cerebrovascular cell pathobiology in AD, and the contribution of microglia inflammation
APOE基因型对AD脑血管细胞病理学的影响以及小胶质细胞炎症的贡献
- 批准号:
10468189 - 财政年份:2021
- 资助金额:
$ 16.2万 - 项目类别:
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