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

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.
项目摘要 老年痴呆症是老年人痴呆症的最常见原因,是一种缓慢但渐进的疾病, 导致神经退化和认知障碍的大脑退化。经典 该疾病的神经病理学标志是含淀粉样蛋白-β(Aβ)的斑块的积累, 当游离Aβ寡聚体形成Ca 2+可渗透孔时导致神经元损伤, 透化和神经元细胞死亡。最近,心血管病理学已经被牵连到 阿尔茨海默病和其他形式的痴呆症的进展。然而,这些疾病 导致阿尔茨海默病的发病机制知之甚少;如何血管功能障碍 可能无法清除老化大脑中的有毒Aβ。我们最近的工作提供了证据, 毛细血管-最小的血管导管和营养输送点和废物清除血液和 周围的神经元-作为一个感觉网络,检测和响应神经活动,促进 局部血流量增加。此外,我们观察到,收缩的成鞘周细胞维持了 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,即Aβ肽对于Ca 2+渗透孔,导致Ca 2+事件的增加, 收缩的周细胞,但不是在附近的血管平滑肌细胞。此外,我们发现Aβ肽- 介导的Ca 2+事件频率的增加导致Ca 2+库耗尽和电压抑制, 门控钙通道。我们建议测试我们的总体假设,即Aβ导致的渐进性损失, 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。本研究的目的是:(1)测试 假设膜脂环境的差异使游离Aβ寡聚体能够形成Ca 2+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Ca 2+储存的假设, 导致STIM 1介导的电压门控性Ca 2+通道抑制; 3)阐明Aβ的作用 低聚物对局部和区域血流的影响。这些研究的成功完成预计将提供 深入了解淀粉样β肽积累如何破坏微环境中的血流, 影响神经元的活力,并为预防神经变性提供治疗靶点, 认知障碍和痴呆症。

项目成果

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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

Pericyte Control of Junctional Blood Flow
周细胞对交界血流的控制
  • 批准号:
    10380521
  • 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:
    10331688
  • 财政年份:
    2021
  • 资助金额:
    $ 51.14万
  • 项目类别:
Pericyte Control of Junctional Blood Flow
周细胞对交界血流的控制
  • 批准号:
    10217229
  • 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:
Pericyte Control of Junctional Blood Flow
周细胞对交界血流的控制
  • 批准号:
    9375422
  • 财政年份:
    2017
  • 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:
    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:
    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:
    7547487
  • 财政年份:
    2008
  • 资助金额:
    $ 51.14万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
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