Behavioral alterations associated with apoptosis and down-regulation of presenilin 1 in the brains of p53-deficient mice

Presenilin 1 (PS1) expression is repressed by the p53 tumor suppressor. As shown herein, wild-type PS1 is an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death. W e analyzed, at the functional and molecular levels, the brains of p53 knock out mice. Surprisingly, we found that lack of p53 expression induces apopto tic brain lesions, accompanied by learning deficiency and behavioral altera tions. p53-deficient mice show an unexpected overexpression of p21(waf1) wi th subsequent down-regulation of PS1 in their brains. This process is progr essive and age-dependent. These data indicate that the p53 pathway, besides affecting tumor suppression, may play a major role in regulating neurobeha vioral function and cell survival in the brain.