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

• 批准号: 10658264
• 负责人: Albert Louis Gonzales
• 金额: $ 51.14万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10658264
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell Membrane Permeability; Cells; Cerebral Amyloid Angiopathy; Cholesterol; Data; Daughter; Dementia; Deterioration; Disease; Electrophysiology (science); Endothelium; Environment; Erythrocytes; Event; Excision; Failure; Frequencies; Functional disorder; Genetically Engineered Mouse; Health; Image; Impaired cognition; Laser Scanning Microscopy; Lead; Lipid Bilayers; Lipids; Mediating; Membrane; Membrane Lipids; Molecular; Morphology; Mus; Muscle Cells; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Omega-3 Fatty Acids; Optics; Pathogenesis; Pathology; Perfusion; Pericytes; Permeability; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Preparation; Prevention; Property; Regional Blood Flow; Resources; Retina; Role; STIM1 gene; Senile Plaques; Sensory; Signal Transduction; Site; Smooth Muscle Myocytes; Stimulus; Supporting Cell; Techniques; Testing; Tissues; Transgenic Mice; Vascular Diseases; Vascular Smooth Muscle; Work; abeta accumulation; abeta oligomer; aging brain; arteriole; cerebral capillary; constriction; hemodynamics; in vivo; in vivo evaluation; insight; mouse model; neural; neuron loss; neuropathology; neurovascular unit; new therapeutic target; novel; pressure; prevent; sensor; therapeutic target; two-photon; voltage; wasting

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.

项目摘要 阿尔茨海默氏症的疾病是衰老成年人痴呆症的最常见原因 - 是一个缓慢而渐进的疾病， 导致神经退行性和认知障碍的大脑恶化。经典 该疾病的神经病理学迹象是淀粉样蛋白β（Aβ）斑块的积累，可以 当游离Aβ低聚物形成Ca2+可渗透孔时，导致神经元损伤，导致膜 透化和神经元细胞死亡。最近，在 阿尔茨海默氏病和其他形式的痴呆症的进展。但是，这些病理如何 对阿尔茨海默氏病的发病机理的贡献知之甚少。血管功能障碍如何 增强无法从衰老大脑中清除有毒Aβ的情况。我们最近的工作提供了证据 毛细血管 - 最小的血管导管以及营养递送和清除血液的点， 周围神经元 - 作为一种感官网络，通过促进神经元活动来检测和反应神经元 局部血流增加。此外，我们观察到收缩时期保持 网络灌注效率通过控制毛细管连接处的血流。在初步结果中，我们 提供新的证据表明Ca2+可渗透孔的Aβ胡椒，导致Ca2+事件的增加 收缩周细胞，但不在附近的血管平滑肌细胞中。另外，我们表明Aβ肽 - 介导的Ca2+事件频率的增加导致Ca2+存储的部署并抑制电压 - 门控Ca2+通道。我们建议检验我们的总体假设，即Aβ导致逐渐丧失 毛细管连接处的周细胞功能，导致毛细血管网络灌注效率降低，最终 影响周围神经元的健康和功能。当前研究的目的是1）测试 假设膜脂质环境的差异使游离Aβ低聚物形成Ca2+可渗透的假设 毛细血管周细胞的毛孔； 2）测试自由Aβ低聚物复制内部Ca2+存储的假设， 导致刺激介导的电压门控Ca2+通道的抑制作用； 3）阐明Aβ的影响 局部和区域血流的低聚物。这些研究的成功完成有望提供 深入了解淀粉样蛋白β肽如何在微环境中累积的血液流动到负面 影响神经元的活力，并为预防导致神经变性的治疗靶标提供 认知障碍和痴呆症。