Angiophagy a mechanism linking microvascular and Alzheimers pathologies

描述(申请人提供)：迟发性认知功能减退可能是多种病理过程的混合体所致。临床、神经病理学和流行病学研究表明，迟发性认知功能减退可能与微血管因素有关。微血管病理作为认知功能下降的潜在机制研究较少，可能是因为缺乏在活体内高分辨率成像微血管的工具，所以在人类中研究它很困难。因此，对于血管和阿尔茨海默氏病之间的潜在协同作用如何发生，仍然没有明确的理解。我们以前发现了一种新的微血管再通机制，称为吞血管作用，涉及血管内皮细胞吞噬栓子，然后它们通过血管壁移位到血管周围空间，导致血流重建。我们提出了一个新的假设，即这种再通机制在微血管和阿尔茨海默病之间的相互作用中起着关键作用。为了验证这些假设，我们开发了复杂而灵敏的实验方法，将阿尔茨海默病小鼠模型与我们的荧光微栓子技术相结合，对栓子和血管进行高分辨率体内和固定组织成像，以及对凝块进行荧光纳米颗粒标记，以便在固定组织中进行长期跟踪。这些实验将极大地提高我们对微血管闭塞和脑淀粉样血管病之间潜在相互作用的理解，淀粉样脑血管病是这些流行疾病之间潜在的关键联系。我们拟议的工作将确定微血管异常和AD病理之间是否存在恶性循环，为治疗开发提供关键的新途径。

DESCRIPTION (provided by applicant): Late onset cognitive decline is likely to be caused by a mixture of pathological processes. Clinical, neuropathological and epidemiological studies suggest that late onset cognitive decline is likely to be linked with microvascular factors. Microvascular pathology has been less studied as a potential mechanism of cognitive decline, perhaps because of difficulties in investigating it in humans due to a lack of tools for imaging microvessels at high resolution in vivo. Thus, there is still no clear understanding as to how the potential synergism between vascular and Alzheimer's pathologies might occur. We have previously discovered a novel mechanism of microvascular recanalization, termed angiophagy, involving the engulfment of emboli by the endothelium followed by their translocation through the vessel wall into the perivascular space leading to flow reestablishment. We propose the novel hypothesis that this mechanism of recanalization plays a critical role in the interactions between microvascular and Alzheimer's pathologies. To test these hypothesis we have developed sophisticated and sensitive experimental methods, combining an Alzheimer's mouse model with our fluorescent microembolization technique, high-resolution in vivo and fixed tissue imaging of emboli and vessels, and fluorescent nanoparticle labeling of clots for long term-tracking in fixed tissues. These set of experiments will greatly improve our understanding of the potential interactions between microvascular occlusion and cerebral amyloid angiopathy a potential critical link between these prevalent conditions. Our proposed work will determine whether there is a vicious cycle between microvascular abnormalities and AD pathology, providing critical novel avenues for therapy development.