ABSTRACT
In tauopathies such as Alzheimer's disease (AD), the moleccular mechanisms of tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the amyloid (Abeta) pathology. Lithium is a medication for bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to lithium. Since lithium directly inhibits glycogen synthase kinase-3beta (GSK3beta), a key enzyme involved in tau phosphorylation, it was suggested that the therapeutic use of lithium could be expanded from mood disorders to neurodegenerative conditions. Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and cognitive impairments in transgenic models of tauopathies. However, the exact mechanism of neuroprotection provided by lithium remains unknown. Here, we show that exposure of cultured cortical neurons to lithium decreased tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains, caspases and proteasome or to neuronal loss, but was rather associated with a reduction in tau mRNA levels. Moreover, prior exposure to lithium, at concentrations effective in reducing tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that lithium could exert its neuroprotective effect against Abeta toxicity through the downregulation of tau proteins and that, at least, by acting at the level of tau mRNA.
Subject(s)
Cerebral Cortex/drug effects , Cytoprotection/drug effects , Down-Regulation/drug effects , Lithium Compounds/pharmacology , Neurons/drug effects , tau Proteins/drug effects , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/toxicity , Animals , Antimanic Agents/pharmacology , Antimanic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/physiology , Cells, Cultured , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Cytoprotection/physiology , Dose-Response Relationship, Drug , Down-Regulation/physiology , Glycogen Synthase Kinase 3/drug effects , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Lithium Compounds/therapeutic use , Neurofibrillary Tangles/drug effects , Neurofibrillary Tangles/metabolism , Neurons/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
PURPOSE: The aim of this study was to investigate microwave (MW) effects on neuronal apoptosis in vitro. MATERIALS AND METHODS: Human neuroblastoma cells SH-SY5Y were exposed to a 900 MHz global system for mobile communication (GSM) or continuous-wave (CW) radiofrequency fields for 24 h in a wire-patch cell. The specific absorption rates (SAR) used were 2 W/kg for CW and 0.25 W/kg average for GSM. During CW exposure, an increase of 2 degrees C was measured, and controls with cells exposed to 39 degrees C were then performed. Apoptosis rate was assessed immediately or 24 h after exposure using three methods: (i) 4',6-diamino-2-phenylindole (DAPI) staining; (ii) flow cytometry using double staining with TdT-mediated dUTP nick-end labeling (TUNEL) and propidium iodide (PI); and (iii) measurement of caspase-3 activity by fluorimetry. RESULTS: No statistically significant difference in the apoptosis rate was observed between sham and 24 h MW-exposed cells, either GSM-900 at an average SAR of 0.25 W/kg, or CW 900 MHz at a SAR of 2 W/kg, either 0 h or 24 h post-exposure. Furthermore, for CW-exposure, apoptosis rates were comparable between sham-, CW-, 37 degrees C- and 39 degrees C-exposed cells. All three methods used to assess apoptosis were concordant. CONCLUSION: These results showed that, under the conditions of the present experiment, MW-exposure (either CW or GSM-900) does not significantly increase the apoptosis rate in the human neuroblastoma cell line SH-SY5Y.
