ABSTRACT Alzheimer's disease (AD) occurs when neurons in the memory and cognition regions of the brain are accompanied by an accumulation of the long amyloid p‐proteins of the 39 to 43 amino acids derived from the amyloid precursor protein (APP) by cleavage with p‐and γ‐secretase. An increased production of Ap‐42 by mutation of PS2 genes promotes caspase expression and is associated with the Cox‐2 found in the brain of AD patients. To address this question in vivo, we expressed the human mutant PS2 (hPS2m ) (N141I) as well as wild PS2 (hPS2w) as a control in transgenic (Tg) mice under control of the neuron‐specific enolase ( NSE ) promoter. Water maze tests were used to demonstrate the behavioral defect; dot blot, Western blot, and immunohistochemical analyses were performed on the brain with the hPS2, Ap‐42, caspase‐3, and Cox‐2 antibody. We concluded that 1) Tg mice showed a behavioral dysfunction in the water maze test, 2) levels of hPS2, Ap‐42, caspase‐3, and Cox‐2 expression were modulated in the brains of both Tg mice, 3) dense staining with antibody to hPS2, Ap‐42, caspase‐3, and Cox‐2 was visible in the brains of Tg mice compared with age‐matched control mice, and 4) distinguishable AD phenotypes between hPS2w‐and hPS2m‐Tg mice did not appear. These results suggest that an elevation of Ap‐42 by overexpression of hPS2 and mutation of hPS2m might induce the behavioral deficit and caspase‐3 and Cox‐2 induction, which could be useful in the therapeutic testing of compounds to have considerable clinical effects.—Hwang, D. Y., Chae, K. R., Kang, T. S., Hwang, J. H., Lim, C. H., Kang, H. K., Goo, J. S., Lee, M. R., Lim, H. J., Min, S. H., Cho, J. Y., Hong, J. T., Song, C. W., Paik, S. G., Cho, J. S., Kim, Y. K. Alterations in behavior, amyloid p‐42, caspase‐3, and Cox‐2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J. 16, 805–813 (2002)