Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75(NTR)-dependent tau hyperphosphorylation in cultured hippocampal neurons

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Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75(NTR)-dependent tau hyperphosphorylation in cultured hippocampal neurons

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Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75(NTR)-dependent tau hyperphosphorylation in cultured hippocampal neurons

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Título: Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75(NTR)-dependent tau hyperphosphorylation in cultured hippocampal neurons
Autor: Sáez, Estefanía T.; Pehar, Mariana; Vargas, Marcelo R.; Barbeito, Luis; Maccioni Baraona, Ricardo Benjamín
Resumen: Reactive astrocytes surround amyloid depositions and degenerating neurons in Alzheimer's disease (AD). It has been previously shown that P-amyloid peptide induces inflammatory-like responses in astrocytes, leading to neuronal pathology. Reactive astrocytes up-regulate nerve growth factor (NGF), which can modulate neuronal survival by signaling through TrkA or p75(NTR) neurotrophin receptor (p75(NTR)). Here, we analyzed whether soluble A beta pepticle 25-35 (A beta) stimulated astrocytic NGF expression, modulating the survival of cultured embryonic hippocampal neurons. Hippocampal astrocytes incubated with A beta up-regulated NGF expression and release to the culture medium. A beta-stimulated astrocytes increased tau phosphorylation and reduced the survival of cocultured hippocampal neurons. Neuronal death and tau phosphorylation were reproduced by conditioned media from A beta-stimulated astrocytes and prevented by caspase inhibitors or blocking antibodies to NGF or p75(NTR). Moreover, exogenous NGF was sufficient to induce tau hyperphosphorylation and death of hippocampal neurons, a phenomenon that was potentiated by a low steady-state concentration of nitric oxide. Our findings show that A beta-activated astrocytes potently stimulate NGF secretion, which in turn causes the death of p75-expressing hippocampal neurons, through a mechanism regulated by nitric oxide. These results suggest a potential role for astrocyte-derived NGF in the progression of AD.
URI: http://www.captura.uchile.cl/handle/2250/6195
Fecha: 2006-10
Cita del item: JOURNAL OF NEUROSCIENCE RESEARCH Volume: 84 Issue: 5 Pages: 1098-1106 Published: OCT 2006


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