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Assessing the Functional Consequences of Tau-Related Vasculature Changes using In Vivo Imaging

使用体内成像评估 Tau 相关脉管系统变化的功能后果

基本信息

批准号：
10629255
负责人：
Rachel Elise Bennett
金额：
$ 24.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10629255
关键词：
APP-PS1 Acute Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Appearance Area Autopsy Biology Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Cell Adhesion Molecules Cell physiology Cells Cephalic Cerebral Amyloid Angiopathy Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Circulation Collaborations Data Dementia Development Diameter Disease model Doxycycline Endothelial Cells Endothelium Erythrocytes Frequencies Functional disorder Gene Expression Goals Hemorrhage Human Imaging Device Impaired cognition Impairment Incidence Individual Inflammation Inflammatory Investigation Label Late Onset Alzheimer Disease Leukocytes Link Location Magnetic Resonance Imaging Measurement Measures Methods Microscopy Modeling Morphology Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Oxygen Partial Pressure Pathologic Pathology Perfusion Photic Stimulation Preparation Proteins Reporting Research Risk Factors Senile Plaques Stroke Tauopathies Techniques Testing Tissues Transgenic Mice Translating Vascular Dementia Vascular Diseases Vascular Endothelium Wild Type Mouse Work abeta accumulation aged angiogenesis awake brain health capillary bed cerebral atrophy cerebral blood volume cerebral hypoperfusion cerebral microvasculature cerebral oxygenation cerebrovascular cohort density experimental study hemodynamics hypoperfusion image translation imaging modality in vivo in vivo imaging mixed dementia mouse model neuroimaging neuron loss novel overexpression phosphorescence promoter recruit response targeted treatment tau Proteins tau aggregation tau expression tissue oxygenation tumor two photon microscopy two-photon

项目摘要

Project Summary/Abstract Vascular changes are increasingly common with age and a risk factor for some forms of cognitive impairment including Alzheimer's disease (AD). In particular, alterations to cerebral perfusion have been widely reported, with decreased blood flow observed in cortical and limbic regions associated with the accumulation of amyloid beta plaques and tau-containing neurofibrillary tangles. Though not expressed by cells that make up cerebral vasculature, the neuronal protein tau has been observed inside of the vascular endothelium in post mortem tissue sections highlighting the intriguing possibility that it may directly affect endothelial cells. In mice, overexpression of tau appears to alter vascular density, reduce average vessel diameter particularly within the capillary bed, and increase the incidence of vessels blocked by leukocytes. These findings could explain, in part, altered cerebral perfusion changes in Alzheimer's disease patients, which may be a key contributor to cognitive decline. The overall goal of this project is to determine how these tau-induced vascular alterations observed in mice affect cerebral perfusion and, ultimately, neurodegeneration. Experiments will be carried out in aging tau overexpressing mice carrying the human P301L mutation (Tg4510 line) and advanced in vivo imaging methods. To assess cerebral perfusion, key measurements will be made in awake mice by two-photon microscopy including red blood cell flow, cerebral oxygenation, and of the hemodynamic response using a visual stimulation paradigm. If tau induces early vascular dysfunction, it will be evident by a reduction in hemodynamic response and poor tissue oxygenation, which will lead to subsequent neuron loss. Further, reduced perfusion could be partially explained by the observation of vessels block by leukocytes. In a second set of experiments, a novel cranial window port method will be used to administer labeled tau and protein directly into the parenchyma to determine if tau is sufficient to increase expression of cell adhesion molecules (CAMs) and induce blood vessel blockages by leukocytes. These investigations will also make use a doxycycline repressible promoter to turn off tau expression in mice and determine if changes in endothelial CAM expression and leukocyte blockage is reversible, which is an important consideration for the development of targeted therapeutics. Findings from these studies will further our understanding of tau biology in non- neuronal subtypes as well as the impact of vascular alterations on brain health more generally, which has broad implications beyond Alzheimer's disease. Finally, by utilizing magnetic resonance imaging methods developed for assessing tumor microvasculature in vivo, we have a unique opportunity to validate the use of these techniques in a neurodegenerative disease model such that we can directly translate the transgenic mouse work to human AD research.! !

项目概要/摘要随着年龄的增长，血管变化越来越常见，并且是某些形式认知障碍的危险因素包括阿尔茨海默病（AD）。特别是脑灌注的改变已被广泛报道，在皮质和边缘区域观察到与淀粉样蛋白积累相关的血流量减少 β 斑块和含有 tau 蛋白的神经原纤维缠结。虽然不由构成大脑的细胞表达在脉管系统中，死后在血管内皮内部观察到神经元蛋白 tau 组织切片强调了它可能直接影响内皮细胞的有趣可能性。在小鼠中， tau 的过度表达似乎会改变血管密度，减少平均血管直径，特别是在血管内毛细血管床，并增加白细胞阻塞血管的发生率。这些发现可以解释，部分，阿尔茨海默氏病患者的脑灌注变化发生改变，这可能是导致认知能力下降。该项目的总体目标是确定这些 tau 蛋白诱导的血管改变是如何发生的在小鼠中观察到影响脑灌注，并最终影响神经退行性变。将进行实验在携带人类 P301L 突变（Tg4510 系）且体内进展的衰老 tau 过度表达小鼠中成像方法。为了评估脑灌注，将通过双光子对清醒小鼠进行关键测量显微镜检查，包括红细胞流动、脑氧合以及使用视觉刺激范式。如果 tau 蛋白诱导早期血管功能障碍，则通过减少血流动力学反应和组织氧合不良，这将导致随后的神经元损失。更远，观察到白细胞阻塞血管可以部分解释灌注减少。一秒钟在一组实验中，将使用一种新颖的颅窗端口方法来施用标记的 tau 蛋白和蛋白质直接进入实质以确定 tau 是否足以增加细胞粘附分子的表达 (CAM) 并诱导白细胞阻塞血管。这些调查还将利用多西环素抑制启动子可关闭小鼠体内的 tau 表达并确定内皮细胞是否发生变化 CAM表达和白细胞阻断是可逆的，这是开发的重要考虑因素的靶向治疗。这些研究的结果将进一步加深我们对非 Tau 生物学的理解。神经元亚型以及血管改变对大脑健康的更广泛影响，除了阿尔茨海默氏病之外，还有广泛的影响。最后，利用磁共振成像方法开发用于评估体内肿瘤微血管，我们有一个独特的机会来验证这些技术用于神经退行性疾病模型，这样我们就可以直接转化转基因小鼠为人类AD研究做出贡献！！

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain Vasculature Accumulates Tau and Is Spatially Related to Tau Tangle Pathology in Alzheimer's Disease.

脑血管系统积累 Tau 蛋白并与阿尔茨海默病中的 Tau 蛋白缠结病理学在空间上相关。

DOI：
10.1101/2024.01.27.577088
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Hoglund,Zachary;Ruiz-Uribe,Nancy;DelSastre,Eric;Woost,Benjamin;Bailey,Joshua;Hyman,BradleyT;Zwang,Theodore;Bennett,RachelE
通讯作者：
Bennett,RachelE

Spatial characterization of tangle-bearing neurons and ghost tangles in the human inferior temporal gyrus with three-dimensional imaging.