Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe neurovascular disfunction. Increasing evidence implicates cerebral microvasculature abnormalities in the genesis of AD neuropathology. Presenilin 1 (PS1) is a protein of central importance to the neuropathology of AD. Mutations in this protein are linked to many cases of autosomal dominant forms of AD. PS1 controls the y-secretase cleavage of several type I transmembrane proteins producing cytoplasmic peptides with signaling and gene expression functions. We recently showed that PS1/y-secretase cleaves ephrinB proteins and promotes the EphB-induced phosphorylation of Src. Since both ephrinB and Src play a critical role in angiogenesis it is possible that PS1/y-secretase may regulate ephrinB-mediated angiogenesis. Here we show that y-secretase promotes the angiogenic response of endothelial cells to EphB in a Src-dependent manner and so does the product of y-secretase cleavage of ephrinB (ephrinB/CTF2 cytoplasmic peptide), whose production is stimulated by EphB receptor. This suggests that PSI/y-secretase may regulate the EphB-induced angiogenesis by cleaving ephrinB and activating Src via this cleavage. To elucidate the mechanism by which PS1/y-secretase promotes the EphB-induced Src activation we analyze the association of ephrinB/CTF2 peptide with the Src regulatory complex. This complex consists of the adaptor protein PAG/Cbp and the regulatory kinase Csk, which regulate the autophosphorylation and activation of Src. We found that ephrinB/CTF2 forms specific complexes with PAG/Cbp affecting its phosphorylation on tyrosine residues and its association with Csk kinase and that PAG/Cbp mediates the EphB-induced angiogenic response of endothelial cells in two in vitro angiogenesis assays. Our data suggest that PS1/y-secretase promotes EphBinduced angiogenesis by cleaving ephrinB, producing ephrinB/CTF2 peptide, which interacts with the Src regulatory machinery promoting Src activation and cell sprouting. Thus PS1/y-secretase may regulate development and integrity of the brain vasculature, and PS1 mutations found in Familial AD may impair it. We propose to examine the role of PSI/y-secretase in the EphB/ephrinB-mediated angiogenesis.

Public Health Relevance

AD is characterized by severe defects in the brain vasculature in regions that are most affected by NFTs and SPs, the hallmark lesions of the disease. PS1 regulates the function of ephrinB, a family of proteins that are critical for development and integrity of brain vasculature and y-secretase promotes the ephrinB-mediated angiogenic response of endothelial cells. The above indicate that PS1/y-secretase may regulate the ephrinB-mediated angiogenesis and that PS1 FAD mutations may impair the angiogenic potential of ephrinB.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
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
Agogo, George O; Ramsey, Christine M; Gnjidic, Danijela et al. (2018) Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout. Int Psychogeriatr 30:1477-1487
Kaur, Antarpreet; Edland, Steven D; Peavy, Guerry M (2018) The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment. Alzheimer Dis Assoc Disord 32:120-124
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Dobbyn, Amanda; Huckins, Laura M; Boocock, James et al. (2018) Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS. Am J Hum Genet 102:1169-1184
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M et al. (2018) A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. J Alzheimers Dis 63:1347-1360
Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53

Showing the most recent 10 out of 555 publications