Abstract
Central nervous system microglia promote neuronal regeneration and sequester toxic β-amyloid (Aβ) deposition during Alzheimer's disease. We show that the cytokine erythropoietin (EPO) decreases the toxic effect of Aβ on microgliain vitro. EPO up-regulates the cysteine-rich glycosylated wingless protein Wnt1 and activates the PI 3-K/Akt1/mTOR/ p70S6K pathway. This in turn increases phosphorylation and cytosol trafficking of Bad, reduces the Bad/Bcl-xL complex and increases the Bcl-xL/Bax complex, thus preventing caspase 1 and caspase 3 activation and apoptosis. Our data may foster development of novel strategies to use cytoprotectants such as EPO for Alzheimer's disease and other degenerative disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / enzymology
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / toxicity*
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Apoptosis / drug effects
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Caspases / metabolism
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Cell Line
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Cytoprotection
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Dose-Response Relationship, Drug
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Enzyme Activation
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Erythropoietin / pharmacology*
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Microglia / drug effects*
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Microglia / enzymology
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Microglia / pathology
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Mitochondria / drug effects
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Mitochondria / enzymology
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Mitochondria / pathology
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / toxicity*
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Phosphatidylinositol 3-Kinase / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Recombinant Proteins / pharmacology
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
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Transfection
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Wnt1 Protein / genetics
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Wnt1 Protein / metabolism*
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bcl-Associated Death Protein / metabolism*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Amyloid beta-Peptides
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EPO protein, human
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Neuroprotective Agents
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Peptide Fragments
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Recombinant Proteins
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WNT1 protein, human
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Wnt1 Protein
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amyloid beta-protein (1-42)
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bcl-Associated Death Protein
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bcl-X Protein
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Erythropoietin
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Caspases