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J. Biol. Chem., Vol. 278, Issue 29, 26687-26694, July 18, 2003
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Presenilin-1, Nicastrin, Amyloid Precursor Protein, and 
-Secretase Activity Are Co-localized in the Lysosomal Membrane*
¶ 
From the
Research Institute,
||Department of Pediatric Laboratory Medicine, The
Hospital for Sick Children, Clinician
Investigator Program, ¶Department of Pathobiology
and Laboratory Medicine, Department of
Biochemistry, University of Toronto, Toronto M5G 1X8, Canada and
**Ciphergen Biosystems Inc., Fremont, California
94555
Alzheimer's disease (AD) is caused by the cerebral deposition of
-amyloid (A), a 38–43-amino acid peptide derived by
proteolytic cleavage of the amyloid precursor protein (APP). Initial studies
indicated that final cleavage of APP by the 
-secretase (a complex
containing presenilin and nicastrin) to produce A occurred in the
endosomal/lysosomal system. However, other studies showing a predominant
endoplasmic reticulum localization of the -secretase proteins and a
neutral pH optimum of in vitro -secretase assays have
challenged this conclusion. We have recently identified nicastrin as a major
lysosomal membrane protein. In the present work, we use Western blotting and
immunogold electron microscopy to demonstrate that significant amounts of
mature nicastrin, presenilin-1, and APP are co-localized with lysosomal
associated membrane protein-1 (cAMP-1) in the outer membranes of lysosomes.
Furthermore, we demonstrate that these membranes contain an acidic
-secretase activity, which is immunoprecipitable with an antibody to
nicastrin. These experiments establish APP, nicastrin, and presenilin-1 as
resident lysosomal membrane proteins and indicate that -secretase is a
lysosomal protease. These data reassert the importance of the
lysosomal/endosomal system in the generation of A and suggest a role for
lysosomes in the pathophysiology of AD.
Received for publication, April 16, 2003 , and in revised form, May 6, 2003.
* This work was supported by a Canadian Institutes for Health Research grant (to J. C. and D. M.) and by a fellowship from the University of Toronto Clinician Scientist Training Program. 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.
To whom correspondence should be addressed: Research Institute, Rm. 9146A Elm
Wing, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G
1X8, Canada. Tel.: 416-813-6161; Fax: 416-813-8700; E-Mail:
hex{at}sickkids.ca.
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