Angiophagy a mechanism linking microvascular and Alzheimers pathologies

描述（由申请人提供）：迟发性认知能力下降可能是由多种病理过程混合引起的。临床、神经病理学和流行病学研究表明，晚发性认知能力下降可能与微血管因素有关。微血管病理学作为认知能力下降的潜在机制的研究较少，这可能是因为由于缺乏高分辨率体内微血管成像工具，在人类中研究它很困难。因此，对于血管和阿尔茨海默病之间的潜在协同作用是如何发生的，仍然没有明确的认识。我们之前已经发现了微血管再通的一种新机制，称为血管吞噬，涉及到栓塞被内皮吞噬，然后它们通过血管壁转移到血管周围空间，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病理之间的相互作用中起着关键作用。为了验证这些假设，我们开发了复杂而敏感的实验方法，将阿尔茨海默氏症小鼠模型与我们的荧光微栓塞技术、栓塞和血管的高分辨率体内和固定组织成像、以及用于长期跟踪固定组织中的血块的荧光纳米颗粒标记相结合。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，这是这些普遍疾病之间潜在的关键联系。我们提出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，为治疗发展提供关键的新途径。

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.