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Acidic-rich region of amyloid precursor protein induces glial cell apoptosis

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Abstract

Amyloid precursor protein (APP) has several caspase cleavage sites in its C-terminal cytoplasmic domain and N-terminal extracellular domain. Caspase cleavages of APP at its cytosolic tail may result in releasing the domain and inducing cell death. During apoptosis, the N-terminal domain may also be processed at amino acids 197 and 219 by caspases leading to unmasking of an acidic-rich region (AR). In this study, AR-exposing APP was shown to inhibit cell growth after transfection into RBA-1 astrocytes and BV-2 microglial cells. The recombinant AR from residue 220 to 288 of APP (APP220–288) was produced and its biological activities were analyzed. APP220–288 induced morphological changes, cell death, and DNA fragmentation in BV-2 and RBA-1 cells. However, AR was determined to have no apparent effects in suspension cells, erythroleukemia K562 cells, and Jurkat T cells. The cytotoxicity was depending on negative charge cluster and the apoptotic activity of AR was attributed to the inhibition of cell adhesion. In BV-2 microglial cells, AR significantly stimulated Fas expression, although expressions of the pro-inflammatory cytokine genes were not detected. APP220–288 also induced nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. These findings indicate that the acidic-rich domain of APP may have apoptotic activity due to inhibition of cell adhesion and induction of iNOS and Fas expressions. Moreover, unmasking the apoptosis-induced AR may activate and exacerbate glial cells which in turn lead to further progression of the death program.

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Authors and Affiliations

  1. Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, 11211

    K.-H. Sun

  2. Division of Urology, Department of Surgery, Tri-service General Hospital, National Defense Medical Center, Taipei, 11100

    G.-H. Sun

  3. Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, 11211

    Y. Su

  4. National Taiwan University Hospital, Taipei, 10000

    C.-I. Chang

  5. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, 20224, Taiwan, Republic of China

    M.-J. Chuang, W.-L. Wu, C.-Y. Chu & S.-J. Tang

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Sun, KH., Sun, GH., Su, Y. et al. Acidic-rich region of amyloid precursor protein induces glial cell apoptosis. Apoptosis 9, 833–841 (2004). https://doi.org/10.1023/B:APPT.0000045793.44842.e7

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  • DOI: https://doi.org/10.1023/B:APPT.0000045793.44842.e7

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