Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics
淀粉样蛋白-β 破坏毛细血管血流动力学的周细胞控制
基本信息
- 批准号:10658264
- 负责人:
- 金额:$ 51.14万
- 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:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloid beta-ProteinBloodBlood VesselsBlood capillariesBlood flowBrainCardiovascular DiseasesCardiovascular PathologyCardiovascular systemCell Membrane PermeabilityCellsCerebral Amyloid AngiopathyCholesterolDataDaughterDementiaDeteriorationDiseaseElectrophysiology (science)EndotheliumEnvironmentErythrocytesEventExcisionFailureFrequenciesFunctional disorderGenetically Engineered MouseHealthImageImpaired cognitionLaser Scanning MicroscopyLeadLipid BilayersLipidsMediatingMembraneMembrane LipidsMolecularMorphologyMusMuscle CellsNerve DegenerationNeurodegenerative DisordersNeuronsNutrientOmega-3 Fatty AcidsOpticsPathogenesisPathologyPerfusionPericytesPermeabilityPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPreparationPreventionPropertyRegional Blood FlowResourcesRetinaRoleSTIM1 geneSenile PlaquesSensorySignal TransductionSiteSmooth Muscle MyocytesStimulusSupporting CellTechniquesTestingTissuesTransgenic MiceVascular DiseasesVascular Smooth MuscleWorkabeta accumulationabeta oligomeraging brainarteriolecerebral capillaryconstrictionhemodynamicsin vivoin vivo evaluationinsightmouse modelneuralneuron lossneuropathologyneurovascular unitnew therapeutic targetnovelpressurepreventsensortherapeutic targettwo-photonvoltagewasting
项目摘要
PROJECT SUMMARY
Alzheimer's Diseases—the most common cause of dementia in aging adults—is a slow, but progressive,
deterioration of the brain that leads to neurodegeneration and cognitive impairment. The classic
neuropathological sign of the disease is the accumulation of amyloid-β (Aβ)-containing plaques, which can
lead to neuronal damage when free Aβ oligomers form Ca2+-permeable pores, causing membrane
permeabilization and neuronal cell death. More recently, cardiovascular pathologies have been implicated in
the progression of Alzheimer's Disease and other forms of dementia. However, how these pathologies
contribute to the pathogenesis of Alzheimer's Disease is poorly understood; how vascular dysfunction
potentiates the failure to clear toxic Aβ from ageing brains. Our recent work provides evidence that
capillaries—the smallest vascular conduits and the point of nutrient delivery and waste removal blood and
surrounding neurons—act as a sensory network that detects and responds to neural activity by promoting an
increase in local blood flow. In addition, we observe that contractile ensheathing pericytes maintain the
efficiency of network perfusion by controlling blood flow at capillary junctions. In Preliminary Results, we
provide new evidence that Aβ peptide for Ca2+ permeable pores, leading to the increases of Ca2+ events in
contractile pericytes, but not in nearby vascular smooth muscle cells. In addition, we show that Aβ peptide-
mediated increases in the frequency of Ca2+ events lead to Ca2+ store depletion and inhibition of the voltage-
gated Ca2+ channels. We propose to test our overarching hypothesis that Aβ leads to the progressive loss of
pericyte function at capillary junctions leading to a reduction in capillary network perfusion efficiency, ultimately
affecting the health and function of surrounding neurons. The aims of the current study are 1) To test the
hypothesis that differences in membrane lipid environments enable free Aβ oligomers to form Ca2+-permeable
pores in capillary pericytes; 2) To test the hypothesis that free Aβ oligomers deplete internal Ca2+ stores,
leading to STIM1-mediated inhibition of voltage-gated Ca2+ channels; and 3) To elucidate the effects of Aβ
oligomers on local and regional blood flow. Successful completion of these studies is expected to provide
insights into how amyloid-β peptide accumulation disrupts blood flow within the microenvironment to negatively
impact neuronal vitality and provide therapeutic targets for the prevention of the neurodegeneration that leads
to cognitive impairment and dementia.
项目总结
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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Albert Louis Gonzales其他文献
Albert Louis Gonzales的其他文献
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{{ truncateString('Albert Louis Gonzales', 18)}}的其他基金
Brain Pericytes and the Progression of Alzheimer's Disease
大脑周细胞与阿尔茨海默病的进展
- 批准号:
10331688 - 财政年份:2021
- 资助金额:
$ 51.14万 - 项目类别:
Brain Pericytes and the Progression of Alzheimer's Disease
大脑周细胞与阿尔茨海默病的进展
- 批准号:
10332753 - 财政年份:2019
- 资助金额:
$ 51.14万 - 项目类别:
Role of TRP channels and calcium signaling in cerebral arteries.
TRP 通道和钙信号在脑动脉中的作用。
- 批准号:
8127689 - 财政年份:2008
- 资助金额:
$ 51.14万 - 项目类别:
Role of TRP channels and calcium signaling in cerebral arteries.
TRP 通道和钙信号在脑动脉中的作用。
- 批准号:
7910472 - 财政年份:2008
- 资助金额:
$ 51.14万 - 项目类别:
Role of TRP channels and calcium signaling in cerebral arteries.
TRP 通道和钙信号在脑动脉中的作用。
- 批准号:
7677356 - 财政年份:2008
- 资助金额:
$ 51.14万 - 项目类别:
Role of TRP channels and calcium signaling in cerebral arteries.
TRP 通道和钙信号在脑动脉中的作用。
- 批准号:
7547487 - 财政年份:2008
- 资助金额:
$ 51.14万 - 项目类别:
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