Since abnormal tau phosphorylation may play a role in neurofibrillary tangle (NFT) formation in aging and Alzheimer's disease (AD), we probed the distribution and abundance of protein phosphatase 2A (PP2A) catalytic (Calpha) and regulatory (PR55alpha and gamma, PR61varepsilon and delta) subunit mRNA in control and AD hippocampus using in situ hybridization. Quantitation of grain density per neuron area of PP2A subunits and beta-actin was determined for the CA3 region of hippocampus and cerebellum, while a qualitative assessment was performed for CA1, CA4, and dentate gyrus. All subunits are expressed in neurons, while PR55gamma and PR55alpha mRNA are also evident in glia. The expression levels of Calpha, all PP2A regulatory subunits studied, and beta-actin were similar in control and AD cerebellum. beta-Actin mRNA was, however, reduced in AD hippocampus. In addition to the generalized reduction of mRNA, as indicated by decreased beta-actin signal, there was a significant loss of Calpha, PR55gamma, and PR61epsilon mRNA in the CA3 hippocampus of AD. This study delineates the distribution of critical PP2A mRNAs and reveals a neuron- and subunit-specific reduction in PP2A catalytic and regulatory mRNA in AD hippocampus. This could result in decreased protein expression and phosphatase activity, leading to the hyperphosphorylation of tau and the formation of NFTs, as well as neuron degeneration in AD.