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Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease

阿尔茨海默病中的脑毛细血管 Piezo1 离子通道和血流调节

基本信息

批准号：
10662664
负责人：
Oliver Bracko
金额：
$ 24.21万
依托单位：
UNIVERSITY OF MIAMI CORAL GABLES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662664
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Architecture Autopsy Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Capillary Endothelial Cell Cell Line Cephalic Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cognitive deficits Data Disease Disease Progression Electrophysiology (science)Embryo Endothelial Cells Endothelium Esthesia Exposure to Foundations Functional disorder Future Genetic Health Image Impairment Ion Channel Life Link Maintenance Measures Mechanics Memory impairment Metabolic Metabolism Molecular Molecular Analysis Mus Neurodegenerative Disorders Neurons Obstruction Patients Pericytes Piezo 1 ion channel Play Probability Proteins Regulation Resolution Risk Factors Role Signal Transduction Stimulus Techniques Testing Three-Dimensional Image Time Translating Western Blotting Wild Type Mouse Work blood-brain barrier permeabilization capillary bed cerebral capillary cerebrovascular constriction end of life endothelial dysfunction flexibility force sensor hemodynamics improved in vivo in vivo imaging innovation insight mechanical force mechanotransduction mouse model neuron loss novel novel therapeutic intervention patch clamp pharmacologic sensor shear stress transcriptome sequencing two photon microscopy two-photon vascular contributions vascular inflammation

项目摘要

Summary: Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease Brain capillaries are the smallest blood vessels in the brain and are crucial in sensing the metabolic needs of active neurons and responding to these needs by supplying more blood. Notably, this function is impaired during neurodegenerative diseases such as Alzheimer’s disease. Not only that capillary sensing is impaired during Alzheimer’s disease, vascular stiffness and complete disruption of capillary blood flow, referred to as capillary stalling, have been observed in mouse models of Alzheimer’s disease. Given that capillary stalling disrupts the hemodynamic forces that capillaries are exposed to, it is important to understand whether Alzheimer’s disease associates with altered mechano-sensing abilities. We recently discovered that the protein Piezo1 is a mechanosensor in brain capillaries. Here, we test the overall hypothesis that altered Piezo1 channel activity is involved in the reduction of brain blood flow in Alzheimer’s disease. We further speculate that tuning Piezo1 activity will improve cerebral blood flow. We will investigate the contribution of endothelial Piezo1 channels to capillary stalling and blood flow reductions in a mouse model of Alzheimer’s disease. Using capillary endothelial cells from wild-type and Alzheimer’s disease mice, we will employ innovative electrophysiological and molecular approaches to assess whether Piezo1 ion channel expression and function are altered during Alzheimer’s disease. In the second aim, we will utilize in vivo high-resolution, two-photon microscopy to investigate capillary stalling and blood flow changes in Alzheimer’s disease mice while pharmacologically manipulating Piezo1 channels. This novel work could lead to new therapeutic strategies not previously tested.

总结：脑毛细血管Piezo1离子通道与阿尔茨海默病的血流调节脑毛细血管是大脑中最小的血管，在感知大脑的代谢需求方面至关重要。激活神经元，并通过供应更多的血液来响应这些需求。值得注意的是，这种功能在神经退行性疾病，如阿尔茨海默病。不仅毛细管感应在阿尔茨海默病，血管僵硬和毛细血管血流完全中断，称为毛细血管在阿尔茨海默氏病的小鼠模型中观察到。考虑到毛细血管停滞破坏了血液动力学的力量，毛细血管暴露，重要的是要了解是否阿尔茨海默病与机械感应能力的改变有关我们最近发现蛋白质Piezo1是一种脑毛细血管中的机械传感器。在这里，我们测试了改变Piezo1通道活性的总体假设，与阿尔茨海默氏症的脑血流量减少有关。我们进一步推测，调整压电1 活动可以改善脑血流量。我们将研究内皮细胞Piezo1通道对毛细血管停滞和血液流动减少在阿尔茨海默氏病的小鼠模型。利用毛细血管内皮细胞从野生型和阿尔茨海默病小鼠，我们将采用创新的电生理和分子评估阿尔茨海默病期间Piezo1离子通道表达和功能是否改变的方法疾病在第二个目标，我们将利用在体高分辨率，双光子显微镜研究毛细血管阿尔茨海默病小鼠在连续操纵Piezo1时的失速和血流变化渠道这项新的工作可能会导致以前没有测试过的新的治疗策略。