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

Amyloid precursor protein (APP) is cleaved to neurotoxic/proinflammatory amyloid β protein (Aβ) or to the neuroprotective secreted α-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 Aβ (1–40) decreases APP secretion into the medium to 10–30% of control values. This decreased secretion appears to be specific for APP since Aβ treatment causes an approximately 2-fold increase in interleukin-8 (IL-8) secretion. Aβ treatment also causes a 4- to 9-fold increase in total cell-associated APP. This increase is due to cellular retention of α secretase-cleaved APP and a 2-fold increase in mature full-length APP. These data suggest that deposition of aggregated Aβ may contribute to Alzheimer’s-associated neurotoxicity by altering the metabolism of the APP protein. Aβ 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.