Induction of Bcl-2 and Bax was related to hyperphosphorylation of tau and neuronal death induced by okadaic acid in rat brain

Authors

  • Li-Qin Chen,

    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    Search for more papers by this author
    • The first 2 authors contributed equally to this paper.

  • Jian-She Wei,

    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    Search for more papers by this author
    • The first 2 authors contributed equally to this paper.

  • Zhi-Nian Lei,

    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    Search for more papers by this author
  • Ling-Mei Zhang,

    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    Search for more papers by this author
  • Yan Liu,

    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    Search for more papers by this author
  • Feng-Yan Sun

    Corresponding author
    1. National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China
    • National Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China
    Search for more papers by this author
    • Fax: 86-21-64174579.


Abstract

Abnormal hyperphosphorylation of the cytoskeletal protein tau is a characteristic feature of neurodegeneration in Alzheimer's disease (AD) brain. Okadaic acid (OA), a protein phosphatase inhibitor, induces neuronal death and hyperphosphorylation of tau. In the present study using a model of microinjection of OA into rat frontal cortex, we aimed to investigate if OA-induced hyperphosphorylation of tau and neuronal death are related to the expression of Bcl-2, an apoptosis inhibitor, or Bax, an apoptosis inducer. Immunohistochemistry and Western blot analysis showed that OA injection dose- and time-dependently induced the expression of Bcl-2 and Bax protein in the surrounding of OA injection areas, which were similar with that of AT8 immunostaining, a marker of hyperphosphorylated tau. However, the ratios of Bcl-2 over Bax had a negative relationship to the expression of AT8. Furthermore, double fluorescent staining showed that AT8-positive neurons mainly costained with terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labeling, a marker of DNA damage, indicating that tau hyperphosphorylation may be associated with DNA damage in the neurons of rat brain. In the areas more adjacent to the OA injection site, most neurons with AT8-positive staining showed vulnerability to OA toxicity and could be triple-stained with Bcl-2 and Bax or double-stained with Bcl-2. However, in the areas further from the OA injection site, neurons with few AT8-positive staining showed resistance to OA toxicity and only stained with Bcl-2, but not Bax. The results suggest that the ratios of Bcl-2 over Bax expression may have an effect on tau hyperphosphorylation and neuronal death following OA injection. © 2005 Wiley-Liss, Inc.

Ancillary