Acidic-rich region of amyloid precursor protein induces glial cell apoptosis.
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.
Sun
K-H
KH
Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11211, Taiwan, Republic of China.
Sun
G-H
GH
Su
Y
Y
Chang
C-I
CI
Chuang
M-J
MJ
Wu
W-L
WL
Chu
C-Y
CY
Tang
S-J
SJ
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004790:Enzyme Induction; D004926:Escherichia coli / Q000235:genetics; D005434:Flow Cytometry; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D019014:fas Receptor; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020169:Caspases