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1.
Org Lett ; 11(19): 4438-40, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19719157

ABSTRACT

The first synthesis of carbon-stapled beta(3)-peptides is reported. The precursor beta(3)-peptides, with O-allyl beta-serines located in an i/i+3 relationship, were prepared on solid phase. We show that efficient ring-closing metathesis (RCM) of these new beta(3)-peptides proceeds smoothly either in solution or on an appropriate solid support. All products were generated with high selectivity for the E-isomer.


Subject(s)
Peptides/chemical synthesis , Cyclization , Peptides/chemistry , Protein Conformation , Protein Structure, Secondary
2.
Brain ; 131(Pt 1): 90-108, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18000012

ABSTRACT

Neuritic abnormalities are a major hallmark of Alzheimer's disease (AD) pathology. Accumulation of beta-amyloid protein (Abeta) in the brain causes changes in neuritic processes in individuals with this disease. In this study, we show that Abeta decreases neurite outgrowth from SH-SY5Y human neuroblastoma cells. To explore molecular pathways by which Abeta alters neurite outgrowth, we examined the activation and localization of RhoA and Rac1 which regulate the level and phosphorylation of the collapsin response mediator protein-2 (CRMP-2). Abeta increased the levels of the GTP-bound (active) form of RhoA in SH-SY5Y cells. This increase in GTP-RhoA correlated with an increase in an alternatively spliced form of CRMP-2 (CRMP-2A) and its threonine phosphorylated form. Both a constitutively active form of Rac1 (CA-Rac1) and the Rho kinase inhibitor, Y27632, decreased levels of the CRMP-2A variant and decreased threonine phosphorylation caused by Abeta stimulation. The amount of tubulin bound to CRMP-2 was decreased in the presence of Abeta but Y27632 increased the levels of tubulin bound to CRMP-2. Increased levels of both RhoA and CRMP-2 were found in neurons surrounding amyloid plaques in the cerebral cortex of the APP(Swe) Tg2576 mice. We found that there was an increase in threonine phosphorylation of CRMP-2 in Tg2576 mice and the increase correlated with a decrease in the ability of CRMP-2 to bind tubulin. The results suggest that Abeta-induced neurite outgrowth inhibition may be initiated through a mechanism in which Abeta causes an increase in Rho GTPase activity which, in turn, phosphorylates CRMP-2 to interfere with tubulin assembly in neurites.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/pharmacology , Intercellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurites/drug effects , rhoA GTP-Binding Protein/physiology , Alzheimer Disease/pathology , Animals , Brain/metabolism , Cell Size/drug effects , GTPase-Activating Proteins/metabolism , Humans , Mice , Mice, Transgenic , Neurites/metabolism , Neurites/ultrastructure , Phosphorylation , Signal Transduction , Tubulin/drug effects , Tubulin/metabolism , Tumor Cells, Cultured , rac1 GTP-Binding Protein/metabolism , rhoA GTP-Binding Protein/metabolism
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