Angiophagy a mechanism linking microvascular and Alzheimers pathologies

血管吞噬是将微血管和阿尔茨海默病病理联系起来的机制

• 批准号: 8919215
• 负责人: Jaime Grutzendler
• 金额: $ 20.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919215
• 关键词: Address; Affect; Affinity; Aging; Alzheimer' s Disease; Amyloid; Amyloid deposition; Arterial Fatty Streak; Basal lamina; Blood Vessels; Blood coagulation; Caliber; Cardiovascular system; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrum; Cessation of life; Cholesterol; Clinical; Coagulation Process; Complex; Data; Deposition; Development; Embolism; Endothelium; Ensure; Epidemiologic Studies; Extravasation; Fibrin; Health; Human; Image; Imaging Device; Impaired cognition; Injection of therapeutic agent; Label; Lead; Life; Link; Location; Measures; Mediator of activation protein; Methods; Mus; Neuronal Injury; Pathologic Processes; Pathology; Pattern; Play; Process; Research; Resolution; Role; Senile Plaques; Site; Staging; System; Techniques; Testing; Therapeutic Embolization; Time; Tissues; Transgenic Mice; Work; amyloid formation; imaging modality; improved; in vivo; insight; microvascular pathology; mouse model; nanoparticle; neurovascular unit; novel; research study; synergism; therapy development; tissue fixing; tool; two-photon

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.

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引起的。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。微血管病理学作为认知能力下降的潜在机制研究较少，这可能是因为缺乏在体内以高分辨率成像微血管的工具而难以在人类中对其进行研究。因此，对于血管和阿尔茨海默病之间的潜在协同作用如何发生仍然没有明确的理解。我们以前已经发现了一种新的微血管再通机制，称为血管吞噬，涉及血栓被内皮细胞吞噬，然后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至关重要的作用。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相结合，高分辨率的栓子和血管的体内和固定组织成像，以及荧光纳米颗粒标记凝块用于固定组织中的长期跟踪。这些实验将大大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，这是这些流行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，为治疗开发提供关键的新途径。