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Production of nerve growth factor by β‐amyloid‐stimulated astrocytes induces p75 NTR ‐dependent tau hyperphosphorylation in cultured hippocampal neurons
Author(s) -
Sáez Estefanía T.,
Pehar Mariana,
Vargas Marcelo R.,
Barbeito Luis,
Maccioni Ricardo B.
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20996
Subject(s) - nerve growth factor , hyperphosphorylation , hippocampal formation , astrocyte , neurotrophin , tropomyosin receptor kinase a , microbiology and biotechnology , low affinity nerve growth factor receptor , biology , neuroscience , nitric oxide , phosphorylation , chemistry , medicine , endocrinology , receptor , central nervous system , biochemistry
Reactive astrocytes surround amyloid depositions and degenerating neurons in Alzheimer's disease (AD). It has been previously shown that β‐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 neurotrophin receptor (p75 NTR ). Here, we analyzed whether soluble Aβ peptide 25–35 (Aβ) stimulated astrocytic NGF expression, modulating the survival of cultured embryonic hippocampal neurons. Hippocampal astrocytes incubated with Aβ up‐regulated NGF expression and release to the culture medium. Aβ‐stimulated astrocytes increased tau phosphorylation and reduced the survival of cocultured hippocampal neurons. Neuronal death and tau phosphorylation were reproduced by conditioned media from Aβ‐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 Aβ‐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. © 2006 Wiley‐Liss, Inc.