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J. Biol. Chem., Vol. 276, Issue 41, 38193-38200, October 12, 2001
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From the Hyperphosphorylated isoforms of the
microtubule-associated protein tau are the major components of
neurofibrillary lesions in Alzheimer's disease (AD). Protein
phosphatase (PP) 2A is a major phosphatase implicated in tau
dephosphorylation in vitro. Dephosphorylation of tau can be
blocked in vivo by okadaic acid, a potent inhibitor of
PP2A. Moreover, activity of PP2A is reduced in AD brains. To elucidate
the role of PP2A in tau phosphorylation and pathogenesis, we expressed
a dominant negative mutant form of the catalytic subunit C
Reduced Protein Phosphatase 2A Activity Induces
Hyperphosphorylation and Altered Compartmentalization of Tau in
Transgenic Mice*
,,, and
Division of Psychiatry Research, University
of Zürich, 8008 Zürich, Switzerland, and the
§ Friedrich-Miescher-Institute, 4002 Basel, Switzerland
of PP2A,
L199P, in mice by using a neuron-specific promoter. We obtained mice
with high expression levels of C L199P in cortical, hippocampal, and
cerebellar neurons. PP2A activity in brain homogenates of transgenic
mice was reduced to 66%. Endogenous tau protein was
hyperphosphorylated at distinct sites including the AT8 epitope
Ser-202/Thr-205, a major AD-associated tau phosphoepitope. AT8-positive
tau aggregates accumulated in the soma and dendrites of cortical
pyramidal cells and cerebellar Purkinje cells and co-localized with
ubiquitin. Our data establish that PP2A plays a crucial role in tau
phosphorylation. Our results also show that reduced PP2A
activity is associated with altered compartmentalization and
ubiquitination of tau, resembling a key pathological finding in AD.
*
This work was supported in part by grants from the Bayer
Alzheimer Research Network (to J. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Psychiatry Research, University of Zürich, August Forel Str. 1, 8008 Zürich, Switzerland. Tel.: 41-1-634-8873; Fax:
41-1-634-8874; E-mail: goetz@ bli.unizh.ch.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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