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Endothelial Pannexin1 in Alzheimer’s Disease

阿尔茨海默病中的内皮 Pannexin1

基本信息

批准号：
10524520
负责人：
Miranda E Good
金额：
$ 48.95万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524520
关键词：
APP-PS1 Adhesions Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Behavioral Biochemical Blood - brain barrier anatomy Blood Vessels Blood flow Brain Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chronic Data Dementia Development Elderly Endothelial Cells Endothelium Experimental Models Extravasation Functional disorder Future Impaired cognition Impairment Infarction Infiltration Inflammation Inflammatory Injury Ischemic Stroke Laser Speckle Imaging Lead Leukocytes LoxP-flanked allele Measures Middle Cerebral Artery Occlusion Mus Myography Neurologic Nucleotides Pathway interactions Patients Pharmacology Phase Proteins Purinoceptor Regulation Reperfusion Therapy Role Senile Plaques Severities Signal Transduction Stains Stroke Structure of posterior cerebral artery TNF gene Testing Therapeutic Intervention Tissues Transgenic Mice Transgenic Organisms Vascular Diseases brain endothelial cell cadherin 5 cell type cerebral artery cerebral hypoperfusion cerebrovascular cognitive development cognitive function cytokine extracellular improved in vivo injured intravital microscopy ischemic injury memory recognition mortality mortality risk mouse model neuroinflammation novel novel therapeutics overexpression pressure prevent response restoration stroke outcome therapeutic target vasoconstriction venule

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease is the most prevalent form of dementia in the elderly and is associated with significantly reduced cerebral blood flow resulting in a chronic state of cerebral hypoperfusion. Patients with Alzheimer’s Disease have increased mortality from ischemic stroke possibly due to preexisting cerebral vascular dysfunction. Thus, it is necessary to examine the mechanisms regulating vascular dysfunction in Alzheimer’s Disease to identify potential therapeutic targets to mitigate cognitive decline and reduce ischemic injury in Alzheimer’s Disease patients. Cerebral arteries become hyperconstrictive in Alzheimer’s Disease and have enhanced responses to nucleotides, such as ATP. Pannexin1 channels in cerebral endothelial cells regulate the release ATP, which subsequently activates downstream purinergic signaling cascades in the vasculature. Pannexin1 protein levels are significantly increased in cerebral tissue from mouse models of Alzheimer’s Disease. We recently discovered that deletion or inhibition of endothelial Pannexin1 reduces cerebral artery myogenic tone to improve cerebral blood flow. In addition to the role in the cerebral arterial vasculature, purinergic signaling is a critical regulator of neuroinflammation in both Alzheimer’s Disease and ischemic stroke. We have also recently demonstrated that deletion of endothelial Pannexin1 profoundly improves post-ischemic stroke infarct volume through a reduction in leukocyte infiltration. Thus, endothelial Pannexin1 is a central regulator of both cerebral arterial vascular tone and post-ischemic stroke inflammation. However, the role of endothelial Pannexin1 in Alzheimer’s Disease and associated ischemic stroke during Alzheimer’s Disease is entirely unknown. We hypothesize that cerebral endothelial Pannexin1 contributes to the development of vascular dysfunction and ischemic stroke severity in Alzheimer’s Disease by increasing vascular tone and inflammation. We will use two aims to test this novel concept. Aim 1 will define the role for endothelial Pannexin1 in regulating cerebral vascular tone and cerebral blood flow during development of Alzheimer’s Disease. Using a mouse model of Alzheimer’s Disease, the APP/PS1 transgenic mice, crossed with our novel transgenic mice conditionally lacking or overexpressing endothelial Pannexin1, we will examine the development of cognitive and biochemical hallmarks of Alzheimer’s Disease and evaluate cerebral arterial myogenic tone and cerebral blood flow. Aim 2 will examine the role of endothelial Pannexin1 in ischemic stroke and neuroinflammation during Alzheimer’s Disease. We will examine ischemic stroke outcome in our transgenic mice with Alzheimer’s Disease, evaluating pre- and post- ischemic stroke neuroinflammation. Successful completion of our study identifying endothelial Panx1 as a novel regulator of cerebral vascular function in Alzheimer’s Disease may provide a target for future therapeutic intervention to improve cognitive function and reduce ischemic stroke injury in Alzheimer’s Disease.

项目总结/文摘