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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：
10437070
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/10437070
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 Circulation Blood Vessels Blood capillaries Blood flow Caliber Cell Adhesion Molecules Cell physiology Cells Cephalic Cerebral Amyloid Angiopathy Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Collaborations Data Dementia Development 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 Lead 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 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 brain parenchyma capillary bed cerebral atrophy cerebral blood volume cerebral hypoperfusion cerebral microvasculature cerebral oxygenation cerebrovascular cohort density experimental study hemodynamics hypoperfusion 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.! !

项目总结/文摘