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.
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.
|Amrock, Levana G; Deiner, Stacie (2014) The implication of frailty on preoperative risk assessment. Curr Opin Anaesthesiol 27:330-5|
|Mitsis, Effie M; Bender, Heidi A; Kostakoglu, Lale et al. (2014) A consecutive case series experience with [18?F] florbetapir PET imaging in an urban dementia center: impact on quality of life, decision making, and disposition. Mol Neurodegener 9:10|
|Lunnon, Katie; Smith, Rebecca; Hannon, Eilis et al. (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci 17:1164-70|
|Dekosky, Steven T; Gandy, Sam (2014) Environmental exposures and the risk for Alzheimer disease: can we identify the smoking guns? JAMA Neurol 71:273-5|
|Roussos, Panos; Mitchell, Amanda C; Voloudakis, Georgios et al. (2014) A role for noncoding variation in schizophrenia. Cell Rep 9:1417-29|
|Ravona-Springer, Ramit; Heymann, Anthony; Schmeidler, James et al. (2014) The ApoE4 genotype modifies the relationship of long-term glycemic control with cognitive functioning in elderly with type 2 diabetes. Eur Neuropsychopharmacol 24:1303-8|
|Jun, Gyungah; Asai, Hirohide; Zeldich, Ella et al. (2014) PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann Neurol 76:379-92|
|Neugroschl, Judith; Sano, Mary; Luo, Xiaodong et al. (2014) Why They Stay: Understanding Research Participant Retention in Studies of Aging, Cognitive Impairment and Dementia. J Gerontol Geriatr Res 3:|
|Babi?, Mirjana; Svob Štrac, Dubravka; Mück-Šeler, Dorotea et al. (2014) Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease. Croat Med J 55:347-65|
|Greenbaum, Lior; Springer, Ramit Ravona; Lutz, Michael W et al. (2014) The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes. Eur Neuropsychopharmacol 24:1492-9|
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