Laurent Pradier

The Long Term Adenoviral Expression of the Human Amyloid Precursor Protein Shows Different Secretase Activities in Rat Cortical Neurons and Astrocytes

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 extracellular and intraneuronal amyloid peptide (Aβ), Aβ was not detected in the culture medium of rat astrocytes producing human WtAPP. Because a low β-secretase activity was previously reported in rodent astrocytes, we wondered whether modifications of the APP amino acid sequence at the β-secretase clipping site would modify the astrocytic production of Aβ. Interestingly, rat astrocytes produced high amounts of Aβ after expression of human APP carrying a double amino acid substitution responsible for Alzheimer’s disease in a large Swedish family (SwAPP). In both rat cortical neurons and astrocytes, the β-secretase cleavage of the human SwAPP occurred very early in the secretion process in a cellular compartment in which a different sorting of SwAPP and WtAPP seems unlikely. These results suggest that human WtAPP and SwAPP could be processed by different β-secretase activities.