Onco-suppressor p53 protein prevents an Alzheimer disease mouse model, Pin1 -null mouse from the increase of presenilin-1

The onco-suppressor p53 protein is essential for checkpoint control in response to a variety of genotoxic stresses. The DNA damage leads to phosphorylation on Ser/Thr-Pro motifs of p53, which facilitates the interaction with Pinl, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pinl is required for the timely accumulation and activation of p53 resulting in apoptosis or cell cycle arrest. Recently it has been indicated that Pin1-null (Pin1-/-) mouse is useful as an Alzheimer disease mouse model. To investigate the pathological relationship between Pinl and p53, we created Pin1-/-p53-/- mice. The thymocytes in 12-week-old Pin1-/-p53-/- mice had significantly higher levels of the intracellular form of Notchl (NIC) than the thymocytes of p53-/- or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full length Notchl was increased in the thymocytes of Pin1-/-p53-/- mice. Presenilin-1 is counted as the enzyme for amyloid β peptides generation in the brain. In the brain of 12-week-old Pin1-/-p53-/- mice, the levels of presenilin-1 were also more than Pin1-/- mice, and disruption of p53 increased presenilin-1 levels of Pin1-/- mice. From these results, it was suggested that p53 might down-regulate presenilin-1 expression and suppress the Aβ generation from Aβ peptide precursor in Pinl-/- mice.