Examining the role of perivascular fibroblasts in cerebral amyloid angiopathy during Alzheimers disease
检查血管周围成纤维细胞在阿尔茨海默病期间脑淀粉样血管病中的作用
基本信息
- 批准号:9897476
- 负责人:
- 金额:$ 19.69万
- 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:2019-04-01 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:Abeta clearanceAbeta synthesisAffectAge-MonthsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorArteriesAutopsyBlood - brain barrier anatomyBlood VesselsBlood flowBrainCarotid Artery Ulcerating PlaqueCellsCerebral Amyloid AngiopathyCerebral cortexChronicDataDementiaDepositionDiseaseEndothelial CellsEnzymesFailureFibroblastsFunctional disorderGene ExpressionGene Expression ProfileGenerationsHealthHemorrhageHeterogeneityImpairmentInflammationIntracranial HemorrhagesLeadLoxP-flanked alleleMeningesMolecularMorphologyMusNeuraxisNeurodegenerative DisordersNeurofibrillary TanglesNeurogliaNeuronsPartner in relationshipPathologyPatientsPopulationProcessProductionReporterReportingResourcesRoleSenile PlaquesStrokeSynapsesTestingTimeTissuesTransgenic MiceWorkabeta accumulationalpha secretaseamyloid precursor protein processingarteriolebeta-site APP cleaving enzyme 1cell typeconditional knockoutdementia riskdisorder controlexperimental studyfrontal lobeglymphatic systeminsightmouse modelneuroinflammationneuron lossnovelpresenilin-1responsesingle cell sequencingsingle-cell RNA sequencingtau Proteinstherapeutic target
项目摘要
ABSTRACT
Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease that is the most common form of
dementia. The pathophysiology of AD includes the progressive loss of neurons and synapses throughout the
cerebral cortex as well as subcortical regions, and is characterized by the buildup of amyloid-beta (Aβ) plaques
and tau-containing neurofibrillary tangle pathologies throughout these regions. Aβ plaques have been reported
to be associated with neuronal and glial cells (parenchymal plaques), or associated with blood vessels
(vascular plaques termed cerebral amyloid angiopathy [CAA]). CAA is found in up to 90% of patients with AD,
and is thought to lead to impaired blood flow, altered vascular morphology, inflammation, microbleeds and
hemorrhage. Despite the importance of CAA, very little is known about how Aβ deposits around vessels.
There are two main hypotheses: First, vascular plaques are generated through the aberrant secretion of Aβ by
endothelial cells and/or mural cells. Second, vascular plaques are generated though dysfunction in clearance
of Aβ. Here we test a novel hypothesis: perivascular fibroblasts secrete Aβ in the generation of CAA. Work in
our lab has identified that perivascular fibroblasts are intimately associated with vascular Aβ plaques in AD
postmortem tissue. We have also identified that that perivascular fibroblasts robustly express amyloid
precursor protein (APP) and the enzymes that process amyloid (BACE1/2, PSEN1). Here, we will use a
conditional knockout approach to determine whether fibroblasts are the key cell type that secretes Aβ in the
generation of CAA in a well characterized mouse model of AD. We will also utilize single cell sequencing to
examine the cellular heterogeneity and gene expression of the perivascular fibroblasts as a function of time in
the mouse AD model. If we find that perivascular fibroblasts are key contributors to Aβ secretion in the buildup
of CAA, then this analysis will give insights into to the mechanism that leads to this vascular Aβ accumulation.
If we find that fibroblast secretion of Aβ is not necessary for the generation of CAA, this analysis will provide
vital information about how the fibroblasts change during the formation of vascular Aβ plaques, with which they
are intimately associated.
摘要
项目成果
期刊论文数量(0)
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Richard Daneman其他文献
Richard Daneman的其他文献
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{{ truncateString('Richard Daneman', 18)}}的其他基金
Identifying the role of notch3 in brain pericyte function in health and Alzheimer's disease
确定 notch3 在健康和阿尔茨海默病中大脑周细胞功能中的作用
- 批准号:
10679198 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
Neurovascular circadian oscillation in health and Alzheimer's disease
健康和阿尔茨海默病中的神经血管昼夜节律振荡
- 批准号:
10655154 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
Neural activity dependent regulation of vascular: implications for Alzheimers disease
神经活动依赖性血管调节:对阿尔茨海默病的影响
- 批准号:
10430716 - 财政年份:2022
- 资助金额:
$ 19.69万 - 项目类别:
Neural activity dependent regulation of vascular: implications for Alzheimers disease
神经活动依赖性血管调节:对阿尔茨海默病的影响
- 批准号:
10641532 - 财政年份:2022
- 资助金额:
$ 19.69万 - 项目类别:
How do CNS fibroblasts regulate the response to neuroinflammation?
中枢神经系统成纤维细胞如何调节对神经炎症的反应?
- 批准号:
10321229 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
How do CNS fibroblasts regulate the response to neuroinflammation?
中枢神经系统成纤维细胞如何调节对神经炎症的反应?
- 批准号:
10543077 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
How do CNS fibroblasts regulate the response to neuroinflammation?
中枢神经系统成纤维细胞如何调节对神经炎症的反应?
- 批准号:
10841263 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
How do CNS fibroblasts regulate the response to neuroinflammation?
中枢神经系统成纤维细胞如何调节对神经炎症的反应?
- 批准号:
10456525 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Blood-brain barrier monoamine metabolism regulation of social behavior
血脑屏障单胺代谢对社会行为的调节
- 批准号:
10170445 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别:
Blood-brain barrier monoamine metabolism regulation of social behavior
血脑屏障单胺代谢对社会行为的调节
- 批准号:
10053133 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别: