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.
|Sano, Mary; Zhu, Carolyn W; Grossman, Hillel et al. (2017) Longitudinal Cognitive Profiles in Diabetes: Results From the National Alzheimer's Coordinating Center's Uniform Data. J Am Geriatr Soc 65:2198-2204|
|Tripodis, Yorghos; Alosco, Michael L; Zirogiannis, Nikolaos et al. (2017) The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. J Alzheimers Dis 59:251-263|
|Brenowitz, Willa D; Hubbard, Rebecca A; Keene, C Dirk et al. (2017) Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample. Alzheimers Dement 13:654-662|
|Jutkowitz, Eric; Kane, Robert L; Gaugler, Joseph E et al. (2017) Societal and Family Lifetime Cost of Dementia: Implications for Policy. J Am Geriatr Soc 65:2169-2175|
|Livny, Abigail; Ravona-Springer, Ramit; Heymann, Anthony et al. (2017) Haptoglobin 1-1 Genotype Modulates the Association of Glycemic Control With Hippocampal Volume in Elderly Individuals With Type 2 Diabetes. Diabetes 66:2927-2932|
|Moheb, Negar; Mendez, Mario F; Kremen, Sarah A et al. (2017) Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia. Dement Geriatr Cogn Disord 43:89-99|
|Monsell, Sarah E; Mock, Charles; Fardo, David W et al. (2017) Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology. Alzheimer Dis Assoc Disord 31:232-238|
|Jiang, Yan; Loh, Yong-Hwee Eddie; Rajarajan, Prashanth et al. (2017) The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat Genet 49:1239-1250|
|Kaur, G; Pawlik, M; Gandy, S E et al. (2017) Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry 22:981-989|
|Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129|
Showing the most recent 10 out of 463 publications