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 (Abeta), Abeta was not detected in the culture medium of rat astrocytes producing human WtAPP. Because a low beta-secretase activity was previously reported in rodent astrocytes, we wondered whether modifications of the APP amino acid sequence at the beta-secretase clipping site would modify the astrocytic production of Abeta. Interestingly, rat astrocytes produced high amounts of Abeta 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 beta-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 beta-secretase activities.
Macq
A F
AF
Laboratory of Experimental Pharmacology, Université Catholique de Louvain, FARL 5410, 54 Avenue Hippocrate, B-1200 Brussels, Belgium.
Czech
C
C
Essalmani
R
R
Brion
J P
JP
Maron
A
A
Mercken
L
L
Pradier
L
L
Octave
J N
JN
D000256:Adenoviridae / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000201:enzymology*; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000201:enzymology*; D051381:Rats; D011995:Recombination, Genetic; D001616:beta-Galactosidase / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D001616:beta-Galactosidase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human