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J. Biol. Chem., Vol. 278, Issue 30, 27688-27694, July 25, 2003
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Peptide Secretion*
¶ ||
From the
Division of Molecular Medicine,
Department of Medicine and the Taub Institute
for Research on Alzheimer's Disease and the Aging Brain, Department of
Pathology, College of Physicians and Surgeons, Columbia University, New York,
New York 10032
A hallmark of Alzheimer's disease is the deposition of plaques of amyloid
peptide (A) in the brain. A is thought to be formed from
the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts,
and cellular cholesterol depletion decreases A formation. The liver X
receptors (LXR) play a key role in regulating genes that control cellular
cholesterol efflux and membrane composition and are widely expressed in cells
of the central nervous system. We show that treatment of APP-expressing cells
with LXR activators reduces the formation of A. LXR activation resulted
in increased levels of the ATP-binding cassette transporter A1 (ABCA1) and
stearoyl CoA desaturase, and expression of these genes individually decreased
formation of A. Expression of ABCA1 led to both decreased
-cleavage product of APPSw (i.e. C99 peptide) and
reduced 
-secretase-cleavage of C99 peptide. Remarkably, these effects
of ABCA1 on APP processing were independent of cellular lipid efflux. LXR and
ABCA1-induced changes in membrane lipid organization had favorable effects on
processing of APP, suggesting a new approach to the treatment of Alzheimer's
disease.
Received for publication, January 23, 2003 , and in revised form, May 15, 2003.
* This work is supported by National Institutes of Health Grants HL 22682 and 54591 (to A. R. T.) and NIA, National Institutes of Health Grant AG18026 (to T.-W. K.). 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.
¶ Ellison Medical Foundation New Scholar in Aging.
|| To whom correspondence should be addressed. Tel.: 212-305-9418; Fax: 212-305-5052; E-mail: art1{at}columbia.edu.
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