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J. Biol. Chem., Vol. 280, Issue 8, 7377-7387, February 25, 2005

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Oxidation of Cholesterol by Amyloid Precursor Protein and -Amyloid Peptide^*

Thomas J. Nelson and Daniel L. Alkon

From the Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850

Alzheimer's disease (AD) is characterized by accumulation of the neurotoxic peptide -amyloid, which is produced by proteolysis of amyloid precursor protein (APP). APP is a large membrane-bound copper-binding protein that is essential in maintaining synaptic function and may play a role in synaptogenesis. -Amyloid has been shown to contribute to the oxidative stress that accompanies AD. Later stages of AD are characterized by neuronal apoptosis. However, the biochemical function of APP and the mechanism of the toxicity of -amyloid are still unclear. In this study, we show that both -amyloid and APP can oxidize cholesterol to form 7-hydroxycholesterol, a proapoptotic oxysterol that was neurotoxic at nanomolar concentrations. 7-Hydroxycholesterol inhibited secretion of soluble APP from cultured rat hippocampal H19–7/IGF-IR neuronal cells and inhibited tumor necrosis factor--converting enzyme -secretase activity but had no effect on -site APP-cleaving enzyme 1 activity. 7-Hydroxycholesterol was also a potent inhibitor of -protein kinase C, with a K_i of 0.2 nM. The rate of reaction between cholesterol and -amyloid was comparable to the rates of cholesterol-metabolizing enzymes (k_cat = 0.211 min^-1). The rate of production of 7-hydroxycholesterol by APP was 200 times lower than by -amyloid. Oxidation of cholesterol was accompanied by stoichiometric production of hydrogen peroxide and required divalent copper. The results suggest that a function of APP may be to produce low levels of 7-hydroxycholesterol. Higher levels produced by -amyloid could contribute to the oxidative stress and cell loss observed in Alzheimer's disease.

Received for publication, August 9, 2004 , and in revised form, December 7, 2004.

^* 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: Blanchette Rockefeller Neurosciences Institute, 317 Academic and Research Bldg., 9601 Medical Center Dr., Rockville, MD 20850. Tel.: 301-294-7178; Fax: 301-294-7007; E-mail: tjnelson{at}brni-jhu.org.

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