Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75NTR-dependent tau hyperphosphorylation in cultured hippocampal neurons.
Reactive astrocytes surround amyloid depositions and degenerating neurons in Alzheimer's disease (AD). It has been previously shown that beta-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 (p75NTR). Here, we analyzed whether soluble Abeta peptide 25-35 (Abeta) stimulated astrocytic NGF expression, modulating the survival of cultured embryonic hippocampal neurons. Hippocampal astrocytes incubated with Abeta up-regulated NGF expression and release to the culture medium. Abeta-stimulated astrocytes increased tau phosphorylation and reduced the survival of cocultured hippocampal neurons. Neuronal death and tau phosphorylation were reproduced by conditioned media from Abeta-stimulated astrocytes and prevented by caspase inhibitors or blocking antibodies to NGF or p75NTR. 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 Abeta-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.
Sáez
Estefanía T
ET
Laboratory of Cellular, Molecular Biology and Neurosciences, Faculty of Sciences, Department Neurological Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Pehar
Mariana
M
Vargas
Marcelo R
MR
Barbeito
Luis
L
Maccioni
Ricardo B
RB
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D017475:Receptors, Nerve Growth Factor; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; D020932:Nerve Growth Factor