Regulation of amyloid precursor protein processing by Aβ in human glioma cells

Amyloid precursor protein (APP) is cleaved to neurotoxic/proinflammatory amyloid beta protein (A beta) or to the neuroprotective secreted alpha-APPs. A balance in APP metabolism may influence the outcome between toxicity and protection to central nervous system (CNS) neurons in Alzheimer's disease. Treatment of U-373 MG astrocytoma cells with aggregated A beta (1-40) decreases APP secretion into the medium to 10-30% of control values. This decreased secretion appears to be specific for APP since AP treatment causes an approximately 2-fold increase in interleukin-8 (IL-8) secretion. A beta treatment also causes a 4- to 9-fold increase in total cell-associated APP. This increase is due to cellular retention of alpha secretase-cleaved APP and a 2-fold increase in mature full-length APP. These data suggest that deposition of aggregated A beta may contribute to Alzheimer's-associated neurotoxicity by altering the metabolism of the APP protein. A beta may exert harmful effects by decreasing the secretion of neuroprotective or neurotrophic APP and, in addition, by increasing intracellular full-length APP; thereby providing increased substrate for generation of amyloidogenic peptide within astrocytes. (C) 2000 Elsevier Science Inc. All rights reserved.