Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics

项目总结 阿尔茨海默氏症--老年人痴呆最常见的原因--是一种缓慢但进行性的疾病， 导致神经退化和认知障碍的大脑退化。经典 这种疾病的神经病理标志是含有淀粉样蛋白(Aβ，Aβ)的斑块积聚，它可以 当游离Aβ寡聚体形成钙离子渗透孔时导致神经元损伤，导致细胞膜 通透性和神经细胞死亡。最近，心血管病理被牵连到 阿尔茨海默病和其他形式的痴呆症的进展。然而，这些病理如何 阿尔茨海默病的发病机制目前知之甚少；血管功能障碍 加剧了无法从老化的大脑中清除有毒的Aβ。我们最近的研究提供了证据 毛细血管-最小的血管管道和营养输送和废物清除的地点血液和 周围神经元-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，收缩包膜周细胞维持 通过控制毛细血管连接处的血流来提高网络灌流的效率。在初步结果中，我们 提供新的证据表明，β多肽对钙离子通透性毛孔，导致钙离子事件的增加。 可收缩的周细胞，但不在附近的血管平滑肌细胞中。此外，我们还证明了Aβ肽- 介导的Ca~(2+)事件频率的增加导致Ca~(2+)储备库耗尽和电压- 门控钙通道。我们建议检验我们的主要假设，即β会导致 毛细血管连接处的周细胞功能最终导致毛细血管网络灌流效率的降低 影响周围神经元的健康和功能。当前研究的目的是：1)测试 膜脂环境差异使游离A-β寡聚体形成钙离子通透性假说 毛细血管周细胞中的孔；2)为了检验游离Aβ寡聚体耗尽内部钙存储的假设， 导致STIM1介导的电压门控钙通道的抑制；以及3)阐明Aβ的作用 对局部和局部血流有影响的低聚物。这些研究的成功完成可望提供 对淀粉样蛋白-β多肽积聚如何扰乱微环境内的血液流动从而产生负面影响的见解 影响神经元活力，为预防神经退行性变提供治疗靶点 认知障碍和痴呆症。

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.