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J. Biol. Chem., Vol. 268, Issue 5, 3021-3024, Feb, 1993
C Haass, AY Hung, MG Schlossmacher, DB Teplow and DJ Selkoe
We have analyzed the cellular processing pathways which produce the 4- kDa
amyloid beta-peptide (A beta) and a 3-kDa derivative (p3) of the
beta-amyloid precursor protein (beta APP) found in conditioned media of
tissue culture cells and in cerebrospinal fluid. Pulse-chase experiments
reveal that both peptides are secreted in parallel with soluble beta APP
(APPs); no precursor-product relation between A beta and p3 was found. The
protease inhibitor leupeptin did not influence the production of either
peptide. In contrast, the weak base ammonium chloride (NH4Cl) showed a
dose-dependent inhibition of A beta production with less decrease in p3. A
similar effect was observed using the monovalent ionophore monensin.
Brefeldin A completely inhibited the generation of both peptides,
indicating that proteases located in the endoplasmic reticulum or early
Golgi are not sufficient for the production of the small peptides. Deletion
of the beta APP cytoplasmic domain, which removes a consensus sequence that
probably mediates reinternalization, caused an increase in secretion of
both APPs and p3 and did not abolish A beta production. These observations
suggest that completely mature beta APP within the late Golgi and/or at the
cell surface is a prerequisite for A beta production but processing within
the lysosome might not be directly required. p3 appears to derive from the
10-kDa C-terminal stub of beta APP following secretion of APPs.
beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms
Department of Neurology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115.
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L. McConlogue, F. Castellano, C. deWit, D. Schenk, and W. A. Maltese Differential Effects of a Rab6 Mutant on Secretory Versus Amyloidogenic Processing of Alzheimer's beta-Amyloid Precursor Protein J. Biol. Chem., January 19, 1996; 271(3): 1343 - 1348. [Abstract] [Full Text] [PDF]
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