Effect of HIV-1 gp41 peptides on secretion of beta-amyloid precursor protein in human astroglial cell line, T98G

To understand the mechanism underlying cognitive deficits in AIDS patients, we examined the influence of gp41 peptides on the expression and the secre tion of Alzheimer's amyloid precursor protein (APP) in human astroglial cel l line T98G. Western blotting analyses demonstrated that treatment of glial cells with a putative immunosuppressive domain (aa 583-599) of gp41 remark ably downregulated the interleukin 1 beta- (IL-1 beta) induced elevation of the secreted form of APP (sAPP alpha) containing Kunitz-type protease inhi bitor (KPI) domain without significant changes of the expression pattern of APP mRNAs as revealed by reverse transcriptase polymerase chain reaction ( RT-PCR) analysis. Recombinant gp41 protein encoding for ectodomain, includi ng aa 583-599 residues, also elicited a similar dose-dependent inhibitory e ffect, whereas the control peptides resulted in little change. The molecula r mechanism underlying this gp41 mediated reduction of sAPP alpha secretion appears not to be owing to the difference in the function of extracellular proteases based on the finding of similar proteolytic activities responsib le for APP metabolism in vitro present in the conditioned media from the cu ltures treated with or without gp41 peptide. However, the known PKC inhibit ors such as H-7 or staurosporine, partially inhibited the elevation of sAPP alpha secretion in response to protein kinase C (PKC) agonist phorbol 12,1 3-dibutyrate (PdBu) as well as to IL-1 beta, mimicking the immunosuppressiv e gp41 peptide. These observations implicate that part of the neurodegenera tive cascade in AIDS brains may involve the inhibitory effect of gp41 on se cretion of sAPP alpha a potent glial neurotrophic factor, through impaired PKC response.