In both, Alzheimer's disease (AD) and frontotemporal dementia (FTD), potein tau is hyperphosphorylated, detaches from the microtubules and forms filaments. Tau is a substrate of protein phosphatase 2A (PP2A). PP2A is a family of heterotrimeric enzymes with diverse functions under physiologic and pathologic conditions. In brains of AD patients, mRNA levels of individual subunits of PP2A have been found to be reduced and to affect PP2A activity, which correlated with tangle load. Since specific inhibition of PP2A in vivo is not possible chemically, we have designed dominant negative transgenic mouse models with altered PP2A composition and/or activity, by overexpression of the mutant catalytic subunits L199P and L309A. Leucine 199 of the catalytic subunit C? is in the catalytic core while the carboxyterminal leucine 309 plays
a crucial role in the recruitment of regulatory subunits into the complex in vitro, a process that determines substrate specificity of PP2A. Our novel transgenic mouse
models, together with the consolidated findings from the present studies on the distribution of PR55/B subunits and their abundance in mice and human cell lines, provide valuable tools to study the role of PR55/B regulatory subunits in PP2A specificity and activity. Our results have thereby facilitated the development and analysis of in vivo models of PP2A function in the brain, have contributed to the understanding of PP2A composition and specificity as well as the development of the lacrimal system, and have further revealed an involvement of PP2A activity in memory
retrieval of mice.