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Role of protein kinase B in Alzheimer's neurofibrillary pathology

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Abstract

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000-g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

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Acknowledgements

Financial support was provided by the Swedish Medical Research Council, Gamla Tjänarinnor Foundation, Greta Lindenau-Hansell Foundation, Loo and Hans Ostermans Foundation, Gun and Bertils Stohnes Foundation, Marianne, Marcus Wallebergs Foundation, Swedish Society for Medical Research, SHMF-9, the Deutsche Forschungsgemeinschaft, and NIH grant AG19158.

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Authors and Affiliations

  1. Neurotec, Section for Experimental Geriatrics, Novum, Karolinska Institutet, KFC Plan 4, 141 86, Huddinge, , Sweden

    Jin-Jing Pei, Wen-Lin An, Maria Nordlinder, Bengt Winblad & Richard F. Cowburn

  2. NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

    Sabiha Khatoon, Inge Grundke-Iqbal & Khalid Iqbal

  3. Department of Neuropsychiatry, Osaka University Medical School, Osaka, Japan

    Toshihisa Tanaka, Ichiro Tsujio & Masatoshi Takeda

  4. Department of Anatomy, J.W. Goethe University, Theodor Stern Kai 7, Frankfurt, Germany

    Heiko Braak

  5. Department of Neuroscience and neurology, Section of Neuropathology, Kuopio University, P.O.BOX 1627, Kuopio, Finland

    Irina Alafuzoff

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  1. Jin-Jing Pei
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Pei, JJ., Khatoon, S., An, WL. et al. Role of protein kinase B in Alzheimer's neurofibrillary pathology. Acta Neuropathol 105, 381–392 (2003). https://doi.org/10.1007/s00401-002-0657-y

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  • DOI: https://doi.org/10.1007/s00401-002-0657-y

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