THE LONG-TERM ADENOVIRAL EXPRESSION OF THE HUMAN AMYLOID PRECURSOR PROTEIN SHOWS DIFFERENT SECRETASE ACTIVITIES IN RAT CORTICAL-NEURONS ANDASTROCYTES

Recombinant adenoviruses were used for the expression of human amyloid precursor protein (APP) of Alzheimer's disease in primary cultures of rat cortical neurons and astrocytes, The catabolic pathways of human APP were studied 3 to 4 days after infection, when the equilibrium of APP production was reached, Although the expression of human wild type APP (WtAPP) by rat neurons induced the production of both extracellul ar and intraneuronal amyloid peptide (A beta), A beta was not detected in the culture medium of rat astrocytes producing human WtAPP. Becaus e a low beta-secretase activity was previously reported in rodent astr ocytes, we wondered whether modifications of the APP amino acid sequen ce at the beta-secretase clipping site would modify the astrocytic pro duction of A beta. Interestingly, rat astrocytes produced high amounts of A beta after expression of human APP carrying a double amino acid substitution responsible for Alzheimer's disease in a large Swedish fa mily (SwAPP), In both rat cortical neurons and astrocytes, the beta-se cretase cleavage of the human SwAPP occurred very early in the secreti on process in a cellular compartment in which a different sorting of S wAPP and WtAPP seems unlikely, These results suggest that human WtAPP and SwAPP could be processed by different beta-secretase activities.