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

• Published in: Apoptosis (London) 2004-11, Vol.9 (6), p.833-841
• Main Authors: Sun, K-H, Sun, G-H, Su, Y, Chang, C-I, Chuang, M-J, Wu, W-L, Chu, C-Y, Tang, S-J
• Format: Article
• Language: English
• Subjects: Adhesion; Amino acids; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - metabolism; Animals; Apoptosis; Caspases - metabolism; Cell Death; Cell Line; Cell Survival; Cells; Cytotoxicity; Enzyme Induction; Escherichia coli - genetics; fas Receptor - metabolism; Flow Cytometry; Mortality; Neuroglia - metabolism; Neuroglia - pathology; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - metabolism; Protein Structure, Tertiary; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transfection
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1023/B:APPT.0000045793.44842.e7

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.