Originally published In Press as doi:10.1074/jbc.M304122200 on May 20, 2003
J. Biol. Chem., Vol. 278, Issue 33, 31261-31268, August 15, 2003
Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular 
-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and A Production*
Olivera M. Grbovic 
¶,
Paul M. Mathews ||,
Ying Jiang ,
Stephen D. Schmidt ,
Ravi Dinakar ,
Nicole B. Summers-Terio ,
Brian P. Ceresa **,
Ralph A. Nixon || and
Anne M. Cataldo 
From the
Center for Dementia Research, Nathan
Kline Institute, Orangeburg, New York 10962, the Departments of
||Psychiatry and
Cell Biology, New York University
School of Medicine, New York, New York 10016, the
**Department of Cell Biology, University of Oklahoma
Health Sciences Center, Oklahoma City, Oklahoma 73104, and the
Laboratory for Molecular Neuropathology,
Mailman Research Center, McLean Hospital, Belmont, Massachusetts 02478 and the
Department of Psychiatry and Neuropathology, Harvard Medical School, Boston,
Massachusetts 02115
We previously identified abnormalities of the endocytic pathway in neurons
as the earliest known pathology in sporadic Alzheimer's disease (AD) and
Down's syndrome brain. In this study, we modeled aspects of these AD-related
endocytic changes in murine L cells by overexpressing Rab5, a positive
regulator of endocytosis. Rab5-transfected cells exhibited abnormally large
endosomes immunoreactive for Rab5 and early endosomal antigen 1, resembling
the endosome morphology seen in affected neurons from AD brain. The levels of
both A
40 and A42 in conditioned medium were increased more than
2.5-fold following Rab5 overexpression. In Rab5 overexpressing cells, the
levels of -cleaved amyloid precursor protein (APP) carboxyl-terminal
fragments (CTF), the rate-limiting proteolytic intermediate in A
generation, were increased up to 2-fold relative to APP holoprotein levels. An
increase in -cleaved soluble APP relative to 
-cleaved soluble APP
was also observed following Rab5 overexpression. CTFs were co-localized
by immunolabeling to vesicular compartments, including the early endosome and
the trans-Golgi network. These results demonstrate a relationship between
endosomal pathway activity, CTF generation, and A production. Our
findings in this model system suggest that the endosomal pathology seen at the
earliest stage of sporadic AD may contribute to APP proteolysis along a
-amyloidogenic pathway.
Received for publication, April 18, 2003
, and in revised form, May 16, 2003.
* This work was supported by National Institutes of Health Grants AG17617,
AG14726, and NS045357, by the Alzheimer Association, and by a Focused Giving
Award from Johnson and Johnson, Inc. The costs of publication of this article
were defrayed in part by the payment of page charges. This article must
therefore be hereby marked "advertisement" in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
These authors contributed equally to this study.
¶
To whom correspondence should be addressed: Memorial Sloan-Kettering Cancer
Center, Dept. for Cell Biology, R1121, 1275 York Ave., New York, NY 10021.
E-mail:
grbovico{at}mskcc.org.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
