A large amount of evidence links brain vascular disorders to cognitive impairment and dementia including Alzheimer's disease (AD). It is believed these defects impair neuronal health and function by restricting transport of nutrients and oxygen to neurons. Additional studies indicate that cerebrovascular dysfunction plays important roles in the pathogenesis of neurodegenerative disorders, a theory also supported by data that the risk of AD increases three fold in stroke patients. Crucial to vascular tissue function and repair is the process of angiogenesis, the generation of new blood vessels from pre-existing vasculature. Angiogenesis is promoted by complex mechanisms including endothelial cell sprouting and plays critical roles in neovascularization, the generation of new blood vessels in damaged tissue. Insufficient angiogenesis in AD brains may represent an important pathogenic mechanism affecting repair of vasculature and leading to neuronal dysfunction. There is now evidence that type 2 diabetes (T2D), a disease also associated with vascular abnormalities in the brain, is a risk factor for dementia. Thus, brain vasculature abnormalities observed in both AD and T2D may provide etiological links between the two disorders. Literature shows that the EphB4/ephrinB2 bidirectional signaling promotes angiogenesis and that the cytoplasmic domain of ephrinB2 is required for this function. Additional reports indicate that endothelial cell sprouting is promoted by angiogenic complexes of Raf-1, Rok-?, and vascular endothelial cadherin (VE- cadherin) and that presenilin1 (PS1) plays important roles in the development, maintenance, and integrity of brain vasculature. Recently, we obtained data that EphB4 stimulates angiogenic complexes between Raf-1, Rok-?, and VE-cadherin and increases sprouting of endothelial cells in vitro in a ?-secretase-dependent manner. In addition, we found that PS1/?-secretase mediates the EphB4-induced cleavage of ephrinB2 and stimulates production of cytoplasmic peptide ephrinB2/CTF2 that regulates cell sprouting. Together, our observations suggest that the PS1/?-secretase system regulates angiogenesis via proteolytic processing of ephrinB2 and production of ephrinB2/CTF2. Here we propose to use animal models to ask whether AD and T2D impair brain neovascularization in response to ischemic injury and whether formation of angiogenic complexes during neovascularization is affected by AD and T2D. In addition, we will examine whether angiogenic complexes in AD and T2D human brains differ from those in normal controls. We will also ask whether peptide ephrinB2/CTF2 promotes neovascularization in vivo and whether it acts as a protective factor against AD- and T2D-linked vascular impairments.

Public Health Relevance

Mount Sinai ADRC: Project 3 Yoon) | NARRATIVE 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. Type 2 diabetes (T2D) is also associated with damage of brain vasculature and interferes with reparative neovascularization. This application asks whether these disorders affect the ability of the brain to repair vascular damage and examines the effects of AD and T2D on mechanisms that promote brain neovascularization and damage repair. Knowledge produced by this work will help to design therapeutic approaches to help healing of the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005138-35
Application #
9716546
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
35
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Wang, Jen-Chyong; Alinaghi, Somayeh; Tafakhori, Abbas et al. (2018) Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation. Neurobiol Aging 62:244.e15-244.e17
Crum, Jana; Wilson, Jeffrey; Sabbagh, Marwan (2018) Does taking statins affect the pathological burden in autopsy-confirmed Alzheimer's dementia? Alzheimers Res Ther 10:104
Wang, Qi; Guo, Lei; Thompson, Paul M et al. (2018) The Added Value of Diffusion-Weighted MRI-Derived Structural Connectome in Evaluating Mild Cognitive Impairment: A Multi-Cohort Validation1. J Alzheimers Dis 64:149-169
Burke, Shanna L; Cadet, Tamara; Maddux, Marlaina (2018) Chronic Health Illnesses as Predictors of Mild Cognitive Impairment Among African American Older Adults. J Natl Med Assoc 110:314-325
Girdhar, Kiran; Hoffman, Gabriel E; Jiang, Yan et al. (2018) Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci 21:1126-1136
Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla et al. (2018) Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. J Alzheimers Dis 62:1815-1826
Wang, Tingyan; Qiu, Robin G; Yu, Ming (2018) Predictive Modeling of the Progression of Alzheimer's Disease with Recurrent Neural Networks. Sci Rep 8:9161
Huang, Qian; Voloudakis, Georgios; Ren, Yimin et al. (2018) Presenilin1/?-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. FASEB J 32:243-253
Hauberg, Mads E; Fullard, John F; Zhu, Lingxue et al. (2018) Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls. Mol Psychiatry :
Giambartolomei, Claudia; Zhenli Liu, Jimmy; Zhang, Wen et al. (2018) A Bayesian framework for multiple trait colocalization from summary association statistics. Bioinformatics 34:2538-2545

Showing the most recent 10 out of 555 publications