BETA-AMYLOID(1-40) INCREASES EXPRESSION OF BETA-AMYLOID PRECURSOR PROTEIN IN NEURONAL HYBRID-CELLS

Studies of cell injury and death in Alzheimer's disease have suggested a prominent role for beta-amyloid peptide (beta-AP), a 40-43-amino-ac id peptide derived from a larger membrane glycoprotein, beta-amyloid p recursor protein (beta-APP). Previous experiments have demonstrated th at beta-AP induces cytotoxicity in a neuronal hybrid cell line (MES 23 .5) in vitro. Here, we demonstrate that beta-APP mRNA content is incre ased 3.5-fold in 24 h after treatment with beta-AP(1-40): Accompanying beta-AP(1-40)-induced cell injury, levels of cell-associated beta-APP and a C-terminal intermediate fragment are increased up to 15-fold, a nd levels of secreted forms of beta-APP and 12- and 4-kDa fragments ar e also increased. Application of beta-APP antisense oligodeoxynucleoti de reduces both cytotoxicity and beta-APP expression. 6-Hydroxydopamin e application or glucose deprivation causes extensive cell damage, but they do not increase beta-APP expression. These results suggest a sel ective positive feedback mechanism whereby beta-AP may induce cytotoxi city and increase levers of potentially neurotrophic as well as amyloi dogenic fragments of beta-APP with the net consequence of further neur onal damage.