PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus

Since abnormal tau phosphorylation may play a role in neurofibrillary tangl e (NFT) formation in aging and Alzheimer's disease (AD), we probed the dist ribution and abundance of protein phosphatase 2A (PP2A) catalytic (Ca) and regulatory (PR55 alpha and gamma, PR61 epsilon and delta) subunit mRNA in c ontrol and AD hippocampus using in situ hybridization. Quantitation of grai n density per neuron area of PP2A subunits and beta -actin was determined f or the CA3 region of hippocampus and cerebellum, while a qualitative assess ment was performed for CA1, CA4, and dentate gyrus, All subunits are expres sed in neurons, while PR55 gamma and PR55 alpha mRNA are also evident in gl ia, The expression levels of C alpha, all PP2A regulatory subunits studied, and beta -actin were similar in control and AD cerebellum. beta -Actin mRN A was, however, reduced in AD hippocampus. In addition to the generalized r eduction of mRNA, as indicated by decreased beta -actin signal, there was a significant loss of C alpha, PR55 gamma, and PR61 epsilon 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 catalyti c and regulatory mRNA in AD hippocampus. This could result in decreased pro tein expression and phosphatase activity, leading to the hyperphosphorylati on of tau and the formation of NFTs, as well as neuron degeneration in AD. (C) 2001 Academic Press.