1,721,089 research outputs found
Endogenous Aβ causes cell death via early tau hyperphosphorylation
No full textAlzheimer's disease (AD) is characterized by A beta overproduction and tau hyperphosphorylation. We report that an early, transient and site-specific AD-like tau hyperphosphorylation at Ser262 and Thr231 epitopes is temporally and causally related with an activation of the endogenous amyloidogenic pathway that we previously reported in hippocampal neurons undergoing cell death upon NGF withdrawal [Matrone, C., Ciotti, M. T., Mercanti, D., Marolda, R., Calissano, P., 2008b. NGF and BDNF signaling control amyloidogenic route and Ab production in hippocampal neurons. Proc. Natl. Acad. Sci. 105, 13138-13143]. Such tau hyperphosphorylation, as well as apoptotic death, is (i) blocked by 4G8 and 6E10 A beta antibodies or by specific beta and/or gamma-secretases inhibitors; (ii) temporally precedes tau cleavage mediated by a delayed (6-12 h after NGF withdrawal) activation of caspase-3 and calpain-I; (iii) under control of Akt-GSK3 beta-mediated signaling. Finally, we show that such site-specific tau hyperphosphorylation causes tau detachment from microtubules and an impairment of mitochondrial traffickin
Endogenous A beta causes cell death via early tau hyperphosphorylation
No full textAlzheimer's disease (AD) is characterized by A beta overproduction and tau hyperphosphorylation. We report that an early, transient and site-specific AD-like tau hyperphosphorylation at Ser262 and Thr231 epitopes is temporally and causally related with an activation of the endogenous amyloidogenic pathway that we previously reported in hippocampal neurons undergoing cell death upon NGF withdrawal [Matrone, C., Ciotti, M. T., Mercanti, D., Marolda, R., Calissano, P., 2008b. NGF and BDNF signaling control amyloidogenic route and Ab production in hippocampal neurons. Proc. Natl. Acad. Sci. 105, 13138-13143]. Such tau hyperphosphorylation, as well as apoptotic death, is (i) blocked by 4G8 and 6E10 A beta antibodies or by specific beta and/or gamma-secretases inhibitors; (ii) temporally precedes tau cleavage mediated by a delayed (6-12 h after NGF withdrawal) activation of caspase-3 and calpain-I; (iii) under control of Akt-GSK3 beta-mediated signaling. Finally, we show that such site-specific tau hyperphosphorylation causes tau detachment from microtubules and an impairment of mitochondrial trafficking.These results depict, for the first time, a rapid interplay between endogenous A beta and tau post-translational modifications which act co-ordinately to compromise neuronal functions in the same neuronal system, under physiological conditions as seen in AD brain. (C) 2009 Elsevier Inc. All rights reserved
A macromolecular structure favouring microtubule assembly in NGF-differentiated pheochromocytoma cells (PC12)
No full textCellular extracts derived from pheochromocytoma cells (PC12-) inhibit the assembly of calf brain tubulin, while those derived from nerve growth factor-differentiated cells (PC12+) do not display this effect. Incubation with RNase abolishes the inhibition by PC12- extracts and reveals the presence of an activating effect exerted by PC12+ extracts. Activation of microtubule assembly is enhanced when extracts are prepared from PC12+ cells exposed for 1 day to 1.0 microM taxol and is abolished when PC12+ extracts are: (a) prepared from cells incubated for 1 day with 1 microM colchicine, (b) treated with the non-ionic detergent Nonidet P-40 or (c) centrifuged at 100 000 g instead of 80 000 g. 2D gel electrophoresis of the proteins of the 100 000 g pellet responsible for the activating effect (referred to as 100 K g pellet) reveals the presence of 100 K, 88 K and 32 K proteins which are markedly enriched in PC12+ extracts. The 88 K protein is further enriched in taxol-treated cells and markedly reduced in the same cells incubated with colchicine. A correlation between the differential protein composition of the 100 K g pellets and their effect on microtubule formation is postulated
Three distinct types of monoclonal antibodies after long-term immunization of rats with mouse nerve growth factor
No full textThis article reports the results of a systematic investigation of the different types of antibodies produced in the course of a long-term immunization of rats with mouse nerve growth factor (NGF). We have characterized three types of monoclonal antibodies, namely: (1) antibodies that bind to NGF and inhibit its binding to target cells and its biological activity in culture (type A); (2) antibodies that bind to and precipitate NGF but do not inhibit its binding to target cells or its biological activity (type B); (3) antibodies that fail to recognize NGF itself, but inhibit nonetheless its binding to target cells (type C). These antibodies bind to an antigen present on NGF target cells and not on rat fibroblasts lacking NGF receptor. They appear thus to be antiidiotypic antibodies directed against the NGF receptor, developed as a consequence of the long-term immunization with NGF
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