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Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors

心血管危险因素增强 CAA 介导的内皮功能障碍

基本信息

批准号：
10427355
负责人：
Silvia Fossati
金额：
$ 56.06万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427355
关键词：
Acetazolamide Address Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid deposition Amyloidosis Animals Apoptotic Behavioral Biochemical Biological Response Modifiers Blood - brain barrier anatomy Blood Vessels Brain Brain Infarction Brain imaging Carbonic Anhydrase Inhibitors Cardiovascular system Cell Death Cells Cellular Stress Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Chemicals Chemosensitization Chronic Clinical Cognitive Complex Dementia Deposition Development Elderly Endothelial Cells Endothelium Epidemiology Exposure to FDA approved Failure Functional disorder Glucose Homocysteine Human Hydrogen Peroxide Hyperhomocysteinemia Hypertension Impaired cognition In Vitro Individual Intervention Link Mediating Mediator of activation protein Methazolamide Microvascular Dysfunction Mitochondria Molecular Mus Nature Nerve Degeneration Neuroimmune Outcome Oxygen Pathogenesis Pathologic Pathway interactions Persons Phenotype Production Public Health Public Health Practice Reactive Oxygen Species Receptor Activation Risk Factors Stress TNF-related apoptosis-inducing ligand TNFRSF10A gene TNFRSF10B gene TNFSF10 gene TREM2 gene Testing Tg2576 Therapeutic Toxic effect Transport Process Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Work abeta deposition base blood damage blood-brain barrier permeabilization brain dysfunction brain endothelial cell cardiovascular risk factor cerebral hypoperfusion cerebrovascular cerebrovascular amyloid cerebrovascular pathology clinical practice cognitive function cytokine endothelial dysfunction enhancing factor hypoperfusion imaging approach in vitro testing in vivo in vivo evaluation mitochondrial dysfunction mixed dementia mouse model neurovascular neurovascular unit non-demented novel overexpression prevent receptor vascular cognitive impairment and dementia β-amyloid burden

项目摘要

Project Summary/Abstract Damage to the brain vasculature significantly contributes to Alzheimer's disease (AD) and dementia. In addition to Cerebral Amyloid Angiopathy (CAA), which is present in more than 90% of AD patients and in many cognitively normal elderly people, chronic cardiovascular (CV) risk factors are also known to impair brain microvascular function. However, the interactive nature of CAA and chronic CV risk factors and the mechanisms through which they contribute to cerebrovascular dysfunction and cognitive decline are poorly understood. Our preliminary work identified molecular mechanisms responsible for amyloid beta (Aβ)-mediated brain endothelial dysfunction. We propose to clarify the interplay between Aβ and overexpression/activation of the TRAIL (TNF-related apoptosis inducing ligand) death receptors (DR) DR4 and DR5, unexplored targets of enormous impact for cell stress/death. DR activation triggers mitochondrial dysfunction, with release of pro- apoptotic factors and reactive oxygen species (ROS). Intriguingly, chronic CV risk factors associated with cerebrovascular pathology, such as hypoperfusion, hypertension and hyperhomocysteinemia (HHC), contribute to similar EC death and mitochondrial dysfunction pathways. We will test the hypothesis that chronic CV risk factors, such as hypertension, HHC, and hypoperfusion, synergistically potentiate the effects of cerebrovascular Aβ in CAA, enhancing TRAIL DR activation and mitochondrial dysfunction in cerebral endothelial cells, and thus leading to neurovascular unit failure in Alzheimer's disease. In Aim 1, using human cerebral endothelial cells in vitro, we will test the hypothesis that chronic CV risk factors increase endothelial vulnerability to Aβ, potentiating DR- and mitochondria-mediated pathways. We will analyze the relative contribution of hypoperfusion and HHC to Aβ-mediated endothelial DR activation, mitochondrial toxicity and BBB permeability through molecular, biochemical and imaging approaches. In Aim 2, we will test in vivo the hypothesis that chronic CV risk factors potentiate DR- and mitochondria-mediated endothelial dysfunction and increase cerebrovascular amyloid burden in a mouse model of amyloidosis, contributing to neurovascular and cognitive impairment. We will assess these mechanisms in Tg2576 mice exposed to chronic CV risk factors (hypertension or HHC) before or after the development of CAA. We will examine the effects of these stress pathways on BBB dysfunction, microhemorrhages, amyloid deposition, neuroimmune activation, and cognitive function. In Aim 3 we will Test the hypothesis that manipulations that decrease DR activation (DR silencing) and mitochondrial dysfunction (carbonic anhydrase inhibitors) will prevent or reverse endothelial damage and BBB permeability induced by the combination of Aβ and chronic cerebrovascular challenges that occur with CV risk. This study will reveal modifiable molecular mechanisms underlying mixed cerebrovascular disease and dementia, which have enormous impact on clinical practice and public health.

项目总结/文摘

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial: Identification of Multiple Targets in the Fight Against Alzheimer's Disease.

社论：识别抗击阿尔茨海默病的多个目标。

DOI：
10.3389/fnagi.2020.00169
发表时间：
2020
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Giannoni,Patrizia;Fossati,Silvia;Marcello,Elena;Claeysen,Sylvie
通讯作者：
Claeysen,Sylvie

Impact of Tau on Neurovascular Pathology in Alzheimer's Disease.

DOI：
10.3389/fneur.2020.573324
发表时间：
2020
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
Canepa E;Fossati S
通讯作者：
Fossati S

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

DOI：
10.3390/cells10112903
发表时间：
2021-10-27
期刊：
Cells
影响因子：
6
作者：
Parodi-Rullán RM;Javadov S;Fossati S
通讯作者：
Fossati S

CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans.

DOI：
10.1176/appi.prcp.20210017
发表时间：
2021
期刊：
Psychiatric research and clinical practice
影响因子：
0
作者：
Ramos-Cejudo J;Genfi A;Abu-Amara D;Debure L;Qian M;Laska E;Siegel C;Milton N;Newman J;Blessing E;Li M;Etkin A;Marmar CR;Fossati S
通讯作者：
Fossati S

Alzheimer's amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain barrier integrity, and angiogenesis.

阿尔茨海默氏症的淀粉样β异质物种差异地影响了脑内皮细胞活力，血脑屏障完整性和血管生成。