PRESENILIN-1 IS INVOLVED IN THE AGE-PROVOKING EFFECT OF REPEATED ETHANOL WITHDRAWAL.

Alcohol is the most abused drug in the United States, and its abuse often creates a medical disorder (alcoholism) of which symptoms include withdrawal syndromes upon the abrupt cessation of drinking. Ethanol withdrawal (EW) syndromes (e.g. anxiety and seizure) are largely hyperexcitatory due to the upregulation of excitatory molecule, glutamate. We have previously demonstrated that repeated exposure to and withdrawal (called repeated EW herein) from ethanol hastens brain aging through increasing stress-activated protein p38. In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW. Supported by NIH/AA018747 and IAADR. Purpose (a): In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Methods (b): Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. Results (c): PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. Conclusions (d): These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW.