ABSTRACT
Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for neurons, however, its effect on A beta-evoked neuronal death has not been examined. We show that the injection of A beta into New Zealand white rabbit brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and the transcription factor, gadd 153. These effects correlate with the activation of JNK and ERK as well as of microglia and with the phosphorylation of tau protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial activation, greatly reduces apoptotic cells, and does not affect the phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and apoptosis triggered by A beta are two independent events, and that the neuroprotective effect of GDNF against A beta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation.
Subject(s)
Amyloid beta-Peptides/pharmacology , CCAAT-Enhancer-Binding Proteins/metabolism , Endoplasmic Reticulum/metabolism , Hippocampus/metabolism , MAP Kinase Signaling System/drug effects , Nerve Growth Factors/pharmacology , Neuroprotective Agents/pharmacology , Peptide Fragments/pharmacology , Transcription Factors/metabolism , Animals , Apoptosis/drug effects , Endoplasmic Reticulum/drug effects , Female , Glial Cell Line-Derived Neurotrophic Factor , Hippocampus/pathology , JNK Mitogen-Activated Protein Kinases , MAP Kinase Signaling System/physiology , Microglia/metabolism , Microglia/pathology , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation/drug effects , Rabbits , Transcription Factor CHOP , tau Proteins/metabolismABSTRACT
Administration of Abeta(1-42) into the rabbit brain induces apoptosis and phosphorylation of tau. These Abeta effects correlate with the activation of JNK and ERK, but not of p38. Treatment with 7 mM lithium inhibits apoptosis, modulates JNK and ERK and does not affect the phosphorylation of tau. Our results demonstrate that lithium, at this dose, effectively inhibits the Abeta-induced apoptosis but has no effect on tau phosphorylation, and that MAP kinases are not involved in the phosphorylation of tau.
Subject(s)
Amyloid beta-Peptides/pharmacology , Hippocampus/enzymology , Lithium/pharmacology , Mitogen-Activated Protein Kinases/metabolism , Peptide Fragments/pharmacology , tau Proteins/metabolism , Alzheimer Disease/enzymology , Amyloid beta-Peptides/metabolism , Animals , Apoptosis/drug effects , Apoptosis/physiology , Enzyme Activation/drug effects , Female , Hippocampus/drug effects , Hippocampus/physiopathology , JNK Mitogen-Activated Protein Kinases , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/drug effects , Neurons/drug effects , Neurons/enzymology , Peptide Fragments/metabolism , Phosphorylation/drug effects , RabbitsABSTRACT
A variety of studies on neuronal death models suggest that lithium has neuroprotective properties. In the present investigation, we have examined the effect of chronic lithium treatment on hippocampus, as monitored by changes at the subcellular level of apoptosis-regulatory proteins which have been induced by the neurotoxin, aluminum maltolate. Intracisternal administration of aluminum into rabbit brain induces cytochrome c release, decreases levels of the anti-apoptotic proteins Bcl-2 and Bcl-X(L), increases levels of the pro-apoptotic Bax, activates caspase-3, and causes DNA fragmentation as measured by the TUNEL assay. Pretreatment for 14 days with 7 mm of lithium carbonate in drinking water prevents aluminum-induced translocation of cytochrome c, and up-regulates Bcl-2 and Bcl-X(L,) down-regulates Bax, abolishes caspase-3 activity and reduces DNA damage. The regulatory effect of lithium on the apoptosis-controlling proteins occurs in both the mitochondria and endoplasmic reticulum. We propose that the neuroprotective effect of lithium involves the modulation of apoptosis-regulatory proteins present in the subcellular organelles of rabbit brain.
