p38 acts as an activator of presenilin 1 in the brain of alcoholic rats.

Purpose: Presenilin 1 (PS1) is originally known as a major protein of which mutation is responsible for age-associated brain disorders such as Alzheimer disease. In addition to this property, interaction between PS1 and other proteins has been reported to mediate various brain damages. Our previous studies have demonstrated that repeated exposure to and withdrawal from a high dose of ethanol provoke the over expression of a stress-activated protein kinase p38 in the rat brains. Here, we investigated whether p38 is an upstream activator of PS1 in a manner that impedes cerebellar-related motoric performance. We also investigated whether p38-PS1 link mediates an excitotoxic stress induced by repeated ethanol exposure and withdrawal. Methods: We employed transgenic mice (p38-KO) lacking p38 in cerebellar neurons and tested motoric performance using Rotarod where a shorter time to fall from rotating apparatus indicates poorer cerebellar function. After Rotarod test, mice were subjected to measure PS1 protein and mRNA level in cerebellum using immunoblot and q-PCR. Separately, young adult male rats (alcoholic rats) received an ethanol program, consisting of 4-week-ethanol diet and 3-week-withdrawal per cycle for two cycles. At the end of the diet program, the rats were tested for Rotarod performance and then cerebellum was used to measure PS1 level. Finally, HT22 (mouse hippocampal) cells were exposed to glutamate with or without a p38 inhibitor to measure PS1 level. Results: P38-KO mice were opposite to alcoholic rats in that they showed a decrease and an increase in the level of PS1 protein and mRNA, accompanied by a superior and inferior motoric performance, respectively. Glutamate treatment increased PS1 level in a manner that is attenuated by a p38 inhibitor. Conclusions: These results suggest that p38 activates PS1, contributing to cerebellar deficit of alcoholic rats. They also suggest that p38-PS1 link is readily formed under a hyperexcitatory stress.