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PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus

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Abstract

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 (Cα) and regulatory (PR55α and γ, PR61ε and δ) subunit mRNA in control and AD hippocampus using in situ hybridization. Quantitation of grain density per neuron area of PP2A subunits and β-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 PR55γ and PR55α mRNA are also evident in glia. The expression levels of Cα, all PP2A regulatory subunits studied, and β-actin were similar in control and AD cerebellum. β-Actin mRNA was, however, reduced in AD hippocampus. In addition to the generalized reduction of mRNA, as indicated by decreased β-actin signal, there was a significant loss of Cα, PR55γ, and PR61ϵ 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.

References (62)

  • M Goedert et al.

    p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease

    FEBS Lett.

    (1992)
  • C Gong et al.

    Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain

    J. Biol. Chem.

    (2000)
  • M Hasegawa et al.

    Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain

    J. Biol. Chem.

    (1992)
  • P Hendrix et al.

    Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing

    J. Biol. Chem.

    (1993)
  • C Kamibayashi et al.

    Comparison of heterotrimeric protein phosphatase 2A containing different B subunits

    J. Biol. Chem.

    (1994)
  • C Kamibayashi et al.

    Expression of the A subunit of protein phosphatase 2A and characterization of its interaction with the catalytic and regulatory subunits

    J. Biol. Chem.

    (1992)
  • E.S Matsuo et al.

    Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau

    Neuron

    (1994)
  • M Mawal-Dewan et al.

    The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases

    J. Biol. Chem.

    (1994)
  • B McCright et al.

    The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm

    J. Biol. Chem.

    (1996)
  • B McCright et al.

    Identification of a new family of protein phosphatase 2A regulatory subunits

    J. Biol. Chem.

    (1995)
  • S.E Merrick et al.

    Site-specific dephosphorylation of tau protein at Ser202/Thr205 in response to microtubule depolymerization in cultured human neurons involves protein phosphatase 2A

    J. Biol. Chem.

    (1996)
  • T.A Millward et al.

    Regulation of protein kinase cascades by protein phosphatase 2A

    Trends Biochem. Sci.

    (1999)
  • J.J Pei et al.

    Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals

    Brain Res.

    (1994)
  • N.E Price et al.

    Brain protein serine/threonine phosphatases

    Curr. Opin. Neurobiol.

    (1999)
  • R Ricciarelli et al.

    Regulation of recombinant PKC alpha activity by protein phosphatase 1 and protein phosphatase 2A

    Arch. Biochem. Biophys.

    (1998)
  • E Sontag et al.

    Molecular interactions among protein phosphatase 2A, tau, and microtubules

    J. Biol. Chem.

    (1999)
  • O Tanabe et al.

    Molecular heterogeneity of the cDNA encoding a 74-kDa regulatory subunit (B" or delta) of human protein phosphatase 2A

    FEBS Lett.

    (1997)
  • Y Zhao et al.

    Saccharomyces cerevisiae homologs of mammalian B and B′ subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions

    J. Biol. Chem.

    (1997)
  • S.E Arnold et al.

    Recent advances in defining the neuropathology of schizophrenia

    Acta Neuropathol. (Berlin)

    (1996)
  • P.V Arriagada et al.

    Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease

    Neurology

    (1992)
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    This work was supported by grants from the NIA, the NIH, and the Dana Foundation.

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    To whom correspondence should be addressed at Maloney 3, HUP, 3600 Spruce Street, Philadelphia, PA 19104-4283. Fax: (215) 349-5909. E-mail: [email protected].

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