Evidence in the last decade implicates cerebral microvasculature abnormalities in the genesis of AD neuropathology. Additional literature shows that the EphB4/ephrinB2 system is an important regulator of the development and function of the vascular system. Binding of the extracellular sequence of EphB4 receptor to its transmembrane ligand ephrinB2 protein on the surface of endothelial cells of blood vessels, stimulates angiogenesis and growth of new vessels from existing vasculature. Furthermore, in vitro assays show that treatment of ephrinB2expressing endothelial cells with the extracellular domain of EphB4 stimulates cell sprouting and tube formation, processes considered crucial initial steps in angiogenesis, while transgenic mouse experiments indicate that the intracellular (cytoplasmic) domain of ephrinB2 protein is necessary for ephrinB2-dependent angiogenesis. We found that EphB4 stimulates the metalloproteinase (MP) and PS/?-secretase processing of ephrinB2 producing cytosolic peptide ephrinB2/CTF2 and that the EphB4-induced sprouting and tube formation of endothelial cells depends on ?-secretase activity. These observations raise the possibility that the endothelial EphB4/ephrinB2 system regulates angiogenesis through PS/?-secretase. In support of this hypothesis, we obtained data that peptide ephrinB2/CTF2 stimulates sprouting of endothelial cells in vitro. Recent literature shows that a crucial step in angiogenic factor-induced angiogenesis is formation of complexes between Raf1/ Rok-? and Vascular Endothelial cadherin (VE-cadherin) and we made the novel observation (preliminary data) that treatment of endothelial cell cultures with EphB4 increases these angiogenic complexes. Together, our observations suggest that PS1/?-secretase may affect angiogenesis by regulating processing of transmembrane protein ephrinB2, a critical step in EphB4-induced angiogenesis. Here we propose to explore the mechanisms via which the EphB4/ephrinB2 and PS1/?-secretase systems interact to promote endothelial cell sprouting and angiogenesis and to examine whether any of these mechanisms are altered in Alzheimer disease (AD) brains. Furthermore, we and others reported that PS1 familial AD (FAD) mutations may affect the epsilon (?) cleavage of PS1/?-secretase substrates thus decreasing production of CTF2 peptides including ephrinB2/CTF2 (see Significance). Thus, we will ask whether PS1 FAD mutants alter the EphB4/ephrinB2-dependent angiogenesis.

Public Health Relevance

Alzheimer Disease (AD) brains show severe defects in the vascular system. It is believed these defects impair neuronal health and function because they restrict transport of nutrients and oxygen to neurons. Research in the last decade showed that protein ephrinB2 regulates development and function of the vascular system and we discovered that Presenilin1 (PS1), a factor important to familial AD, interacts with ephrinB2 and regulates it vascular functions. This application examines the mechanisms by which PS1 and ephrinB2 regulate the vascular system with the ultimate aim of discovering methods to correct defects of brain vasculature.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047229-13
Application #
9395949
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
2004-01-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Bruban, Julien; Voloudakis, Georgios; Huang, Qian et al. (2015) Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via ?-secretase-independent transcriptional mechanisms. FASEB J 29:3702-12
Robakis, Nikolaos K; Georgakopoulos, Anastasios (2014) Allelic interference: a mechanism for trans-dominant transmission of loss of function in the neurodegeneration of familial Alzheimer's disease. Neurodegener Dis 13:126-30
Roussos, Panos; Mitchell, Amanda C; Voloudakis, Georgios et al. (2014) A role for noncoding variation in schizophrenia. Cell Rep 9:1417-29
Barthet, Gael; Dunys, Julie; Shao, Zhiping et al. (2013) Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 34:499-510
Xuan, Zhao; Barthet, Gael; Shioi, Junichi et al. (2013) Presenilin-1/?-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B. J Biol Chem 288:30495-501
Zhu, Li; Zhong, Minghao; Zhao, Jiaying et al. (2013) Reduction of synaptojanin 1 accelerates A? clearance and attenuates cognitive deterioration in an Alzheimer mouse model. J Biol Chem 288:32050-63
Barthet, Gael; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2012) Cellular mechanisms of ýý-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166-75
Xu, Jindong; Xilouri, Maria; Bruban, Julien et al. (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326.e5-16
Barthet, Gael; Shioi, Junichi; Shao, Zhiping et al. (2011) Inhibitors of ýý-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. FASEB J 25:2937-46

Showing the most recent 10 out of 18 publications