AMYLOID PRECURSOR PROTEIN TRUNCATED AT ANY OF THE GAMMA-SECRETASE SITES IS NOT CLEAVED TO BETA-AMYLOID

Citation
Pa. Paganetti et al., AMYLOID PRECURSOR PROTEIN TRUNCATED AT ANY OF THE GAMMA-SECRETASE SITES IS NOT CLEAVED TO BETA-AMYLOID, Journal of neuroscience research, 46(3), 1996, pp. 283-293
Citations number
34
Categorie Soggetti
Neurosciences
ISSN journal
03604012
Volume
46
Issue
3
Year of publication
1996
Pages
283 - 293
Database
ISI
SICI code
0360-4012(1996)46:3<283:APPTAA>2.0.ZU;2-O
Abstract
beta A4 secretion occurs upon processing of amyloid protein precursor (APP) by beta-secretase (N-terminus of beta A4) and gamma-secretase (C -terminus), To determine the sequence of these activities and the proc essing intermediate of beta A4, we expressed several truncated APP mol ecules in human HEK-293 cells, Immunofluorescence and biotinylation st udies indicated that full-length APP or APP lacking the cytosolic doma in both were located intracellularly, associated with the cell surface and secreted, APPs truncated after amino acid 40, 42, or 43 of beta A 4 were not inserted into cell membranes, were found intracellularly bu t not on the cell surface, and were efficiently secreted into the cult ure medium, The secretion of APP truncated at amino acid 40 of beta A4 occurred without proteolytic processing, Neither beta A4 nor P3 (the product of the alpha-secretase) was secreted from any of the APP molec ules truncated at the gamma-secretase sites, In sharp contrast to this , when the C-terminal 100 amino acids of APP were expressed (APP trunc ated at the N-terminus of beta A4), a robust beta A4 secretion was obs erved, Thus, the C-terminal fragment of APP produced by beta-secretase activity is likely to be the processing intermediate of beta A4. (C) 1996 Wiley-Liss, Inc.