权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Presenilin1/gamma-secretase regulate the VEGFA/VEGFR2 brain angiogenesis inhibited by FAD mutants.

Presenilin1/γ-分泌酶调节 FAD 突变体抑制的 VEGFA/VEGFR2 脑血管生成。

基本信息

批准号：
10913858
负责人：
Anastasios Georgakopoulos
金额：
$ 83.49万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-08-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10913858
关键词：
Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Angiogenesis Inhibition Angiogenic Factor Area Atrophic Attenuated Binding Blood Circulation Blood Vessels Blood capillaries Blood flow Brain Brain Hypoxia-Ischemia Cadherins Cell Separation Cerebrovascular Disorders Cerebrovascular system Chronic Complex Data Dementia Development Diameter Dimerization Endothelial Cells Endothelial Growth Factors Receptor Endothelium Ephrin B Receptor Ephrins Functional disorder Generations Genetic Growth Growth Factor Health Human Impaired cognition Impairment Ischemia KDR gene Lesion Life Ligands Link Mediating Membrane Metabolic Metalloproteases Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Organ Pathogenesis Pathologic Peptide Hydrolases Phosphorylation Play Process Protein Family Proteins Regulation Reporting Role Signal Transduction System Testing Tissues Tube VEGFA gene Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular System Vascular blood supply angiogenesis brain abnormalities brain endothelial cell brain repair brain tissue cell motility density familial Alzheimer disease gamma secretase ischemic injury ischemic lesion mind control mouse model mutant neovascularization neuroimaging neuron loss neuronal survival neurovascular novel therapeutic intervention presenilin protein complex prototype receptor repaired tissue repair vascular abnormality vascular injury

项目摘要

Summary The cerebrovascular system is central to neuronal survival and function and recent evidence suggests that vascular brain abnormalities are involved in the development and neuropathophysiology of neurodegenerative disorders such as Alzheimer disease (AD). Angiogenesis, the generation of new blood vessels from existing vasculature, is crucial throughout adult life for maintaining brain blood circulation and for reparative mechanisms of toxic insults such as ischemia and hypoxia. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factors (VEGFs). By binding to their receptors (VEGFRs), VEGFs regulate formation of new blood vessels and maintain blood supply to tissues and organs. Mutants of the protein Presenilin1 (PS1) cause Familial AD (FAD) constituting a system where mechanisms of AD-like neurodegeneration can be studied. A normal function of PS1 is to act as a protease, called γ-secretase, which processes type I membrane receptors. Here we present evidence that the PS1/γ-secretase system processes VEGFR2 that is known to play crucial roles in the regulation of the vascular system, including the brain vasculature. Critical angiogenic functions of VEGFR2 include its dimerization, internalization and downstream angiogenic signaling of endothelial cells (ECs). We also found that inhibition of the γ-secretase activity decreases the VEGFA-induced dimerization of VEGFR2 and the VEGFR2-mediated angiogenenic functions of primary cortical ECs (pCECs) such as sprouting, tube formation, cell migration and angiogenic complex formation. Together, our data suggest that γ-secretase regulates the VEGFA-stimulated angiogenic functions of VEGFR2. Importantly, we found that PS1 FAD mutants decrease the VEGFA-induced γ-secretase processing and dimerization of VEGFR2 and the VEGFA-stimulated angiogenic signaling and functions of ECs. Together, our data indicate that PS1 FAD mutants attenuate the VEGFA-induced angiogenic functions of brain ECs suggesting a mechanism by which FAD mutants cause neuronal dysfunction and death by decreasing angiogenic functions and tissue repair of the brain. In this application, we explore the interactions of PS1 and its FAD mutants with VEGFR2 and explore the importance of this interaction to the VEGFA-induced and VEGFR2-mediated angiogenenic signaling and functions of the brain. We also use mouse models to examine mechanisms by which γ-secretase activity regulates angiogenic signaling of the VEGFA/VEGFR2 system, and test the roles of PS1 and PS1FAD mutants in the VEGFA- and ischemia-stimulated brain angiogenesis. We also explore signatures of angiogenic dysfunction in human FAD and sporadic AD brain tissue.