Presenilin 2 (PS2), the chromosome 1 familial Alzheimer's disease gene, has been shown to sensitize differentiated PC12 (dPC12) cells to apoptosis. In this investigation we show that activation of the p38 mitogen activated protein kinase pathway occurs downstream of PS2 and is required for sensitizing the cells to apoptosis. Overexpression of PS2 led to a dramatic increase in p38 activity, which is correlated with an increased susceptibility of dPC12 cells to apoptosis. Inhibition of p38 by the specific inhibitor SB203580 or interfering with the p38 pathway by overexpression of dominant negative MKK6 effectively blocked PS2 sensitized apoptosis. Expression of ALG-3, a truncated PS2 which acts as a dominant negative PS2, significantly suppressed p38 activation induced by trophic factor withdrawal. These data suggest that PS2 is a signaling molecule upstream of the p38 MAPK pathway in apoptotic dPC12 cells.