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(Received for publication, March 31, 1997, and in revised form, May 5, 1997)
From the Amyloid
Volume 272, Number 26,
Issue of June 27, 1997
pp. 16085-16088
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
-Peptide Terminating at Amino Acid 42
,
,
,
,
Central Institute of Mental Health,
Department of Molecular Biology, J5, 68159 Mannheim, Germany and the
¶ Department of Neuropathology, Institute for Brain Research,
Faculty of Medicine, University of Tokyo, Tokyo 113, Japan
-peptide (A) is known to accumulate
in senile plaques of Alzheimer's disease (AD) patients and is now
widely believed to play a major role in the disease. Two populations of
peptides occur terminating either at amino acid 40 or at amino acid 42 (A1-40 and A1-42). Alternative N-terminal cleavages produce additional heterogeneity (Ax-40 and
Ax-42). Peptides terminating at amino acid 42 are
believed to be the major player in sporadic AD as well as familial AD
(FAD). Whereas the cellular mechanism for the generation of A
terminating at amino acid 40 is well understood, very little is known
about the cleavage of A after amino acid 42. By using two
independent methods we demonstrate intracellular A1-42 as well as
Ax-42 but less Ax-40 and A1-40 in
kidney 293 cells stably transfected with wild type -amyloid precursor protein (APP) or the FAD-associated Val/Gly mutation. Moreover, retention of APP within the endoplasmic reticulum (ER) by
treatment with brefeldin A does not block the cleavage at amino acid 42 but results in an increased production of all species of A
terminating at amino acid 42. This indicates that the cleavage after
amino acid 42 can occur within the ER. Treatment of cells with
monensin, which blocks transport of (APP) within the Golgi causes a
marked accumulation of intracellular Ax-42 and
Ax-40. Therefore these experiments indicate that the
-secretase cleavage of A after amino acid 42 can occur within the
ER and later within the secretory pathway within the Golgi.
Moreover inhibition of reinternalization by cytoplasmic deletions of
APP as well as inhibition of intracellular acidification by
NH4Cl does not block intracellular A1-42 or
Ax-42 production.
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