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.

项目概要 阿尔茨海默氏病是老年人痴呆症的最常见原因，是一种缓慢但进行性的疾病 大脑退化导致神经退行性变和认知障碍。经典之作 该疾病的神经病理学标志是含有淀粉样蛋白 - β (Aβ) 的斑块的积累，这可以 当游离 Aβ 寡聚体形成 Ca2+ 渗透性孔，导致膜形成时，会导致神经元损伤 透化和神经元细胞死亡。最近，心血管疾病与 阿尔茨海默病和其他形式的痴呆症的进展。然而，这些病症如何 人们对阿尔茨海默氏病的发病机制知之甚少；血管功能障碍怎么办 加剧了从老化大脑中清除有毒 Aβ 的失败。我们最近的工作提供了证据表明 毛细血管——最小的血管导管，也是营养物质输送和废物清除血液和血液的点 周围的神经元——充当感觉网络，通过促进神经活动来检测和响应神经活动 局部血流量增加。此外，我们观察到收缩鞘周细胞维持 通过控制毛细血管连接处的血流来提高网络灌注的效率。在初步结果中，我们 提供了新的证据表明Aβ肽对Ca2+渗透孔，导致Ca2+事件的增加 收缩的周细胞，但不在附近的血管平滑肌细胞中。此外，我们还发现 Aβ 肽- 介导的 Ca2+ 事件频率增加导致 Ca2+ 储存耗尽并抑制电压- 门控 Ca2+ 通道。我们建议检验我们的总体假设，即 Aβ 会导致 Aβ 逐渐丧失 毛细血管连接处的周细胞功能最终导致毛细血管网络灌注效率降低 影响周围神经元的健康和功能。当前研究的目的是 1) 测试 假设膜脂环境的差异使游离 Aβ 寡聚体形成 Ca2+ 渗透性 毛细血管周细胞中的孔； 2) 为了检验游离 Aβ 寡聚体耗尽内部 Ca2+ 储存的假设， 导致 STIM1 介导的电压门控 Ca2+ 通道抑制； 3) 阐明 Aβ 的作用 寡聚物对局部和区域血流的影响。成功完成这些研究预计将提供 深入了解淀粉样β肽积累如何扰乱微环境内的血流，从而产生负面影响 影响神经元活力并为预防导致神经退行性疾病提供治疗靶点 导致认知障碍和痴呆。