Current Biology
Research PaperAlzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells
Section snippets
Background:
The mechanisms that result in neuronal loss in Alzheimer's disease are not understood. The discovery of several different mutations in the gene for the amyloid precursor protein in some pedigrees with familial Alzheimer's disease has given support to the ‘amyloid cascade’ hypothesis, in which the extracellular deposition of β-amyloid is an early pathogenic event (see [1], [2], [3] for reviews). A consensus has not yet been reached, however, on how deposition of β-amyloid in the brain results in
Discussion
In current hypotheses regarding the molecular pathology of Alzheimer's disease, aberrant amyloid precursor protein metabolism and the deposition of β-amyloid is placed as a primary pathogenic event (reviewed in [1], [2], [3]). It is becoming increasingly apparent, however, that cognitive deficits do not occur until dystrophic neurites containing PHFs and neurofibrillary tangles have developed [32], [33]. The transformation of tau to a hyperphosphorylated state as found in PHFs may thus
Primary neuronal cultures and transfection of COS-7 cells
Primary neuronal cultures derived from E17 (embryonic day 17) foetal rat brain cortices were prepared following standard protocols and plated at 3.2 times 105 cells cm−2 on dishes precoated with 10 mg ml−1 poly-L-lysine and 10 mg ml−1 laminin (Sigma) in glutamine-free culture medium comprising DMEM and Ham's F12 (4:1) supplemented with 100 mg ml−1 transferrin, 60 mM putrescine, 5 mg ml−1 insulin, 20 nM sodium selenite, 100 IU penicillin and 100 μg ml−1 streptomycin and 2% horse serum.
After 1
Acknowledgements
This research was funded by grants from the MRC, The Wellcome Trust and the Nuffield Foundation (to C.C.J.M.), a Wellcome Trust Programme grant (to B.H.A., C.C.J.M. and J-M.G), grants from the Commission of European Union and Glaxo Group research (to B.H.A) and a grant from The Wolfson Foundation (to C.C.J.M. and B.H.A). S.L. is supported by a Wellcome Trust Training Fellowship. We thank M. Weber, University of Virginia Health Sciences Center, Charlottesville, for kindly supplying a cDNA
Simon Lovestone, C. Hugh Reynolds, Donna Latimer, Daniel R. Davis, Brian H. Anderton, Diane Hanger, Sandrine Mulot and Christopher C.J. Miller (corresponding author), Department of Neuroscience, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Jean-Marc Gallo, Department of Neurology, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Betina Marquardt and Silvia Stabel, Max-Delbruck-Laboratorium, Carl-von-Linne-Weg 10, D-50829 Koln,
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Cited by (0)
Simon Lovestone, C. Hugh Reynolds, Donna Latimer, Daniel R. Davis, Brian H. Anderton, Diane Hanger, Sandrine Mulot and Christopher C.J. Miller (corresponding author), Department of Neuroscience, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Jean-Marc Gallo, Department of Neurology, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Betina Marquardt and Silvia Stabel, Max-Delbruck-Laboratorium, Carl-von-Linne-Weg 10, D-50829 Koln, Germany.
James R. Woodgett, Ontario Cancer Reseach Institute/Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario M4X 1K9, Canada.