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The Journal of Neuroscience, October 3, 2007, 27(40):10895-10905; doi:10.1523/JNEUROSCI.3135-07.2007

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Neurobiology of Disease
The Metalloprotease Inhibitor TIMP-3 Regulates Amyloid Precursor Protein and Apolipoprotein E Receptor Proteolysis

Hyang-Sook Hoe,¹ Matthew J. Cooper,¹ Mark P. Burns,¹ Patrick A. Lewis,³ Marcel van der Brug,³ Geetanjali Chakraborty,¹ Casandra M. Cartagena,¹ Daniel T. S. Pak,² Mark R. Cookson,³ and G. William Rebeck¹

Departments of ¹Neuroscience and ²Pharmacology, Georgetown University Medical Center, Washington, DC 20057-1464, and ³Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707

Correspondence should be addressed to G. William Rebeck, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057-1464. Email: gwr2{at}georgetown.edu

Cellular cholesterol levels alter the processing of the amyloid precursor protein (APP) to produce Aß. Activation of liver X receptors (LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter Aß levels in vitro and in vivo. To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist (TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 (ADAM-10) and ADAM-17, two APP -secretases. We found that TIMP-3 inhibited -secretase cleavage of APP and an apolipoprotein E (apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP ß-C-terminal fragment and Aß production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and -secretase cleavage and encourages endocytosis and ß-secretase cleavage. In vivo, TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease (AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of Aß.

Key words: Alzheimer's disease; secretase; LXR; apolipoprotein; amyloid; neurodegeneration

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Received March 7, 2007; revised Aug. 8, 2007; accepted Aug. 20, 2007.

Correspondence should be addressed to G. William Rebeck, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057-1464. Email: gwr2{at}georgetown.edu

This article has been cited by other articles:

				H.-S. Hoe, S. S. Minami, A. Makarova, J. Lee, B. T. Hyman, Y. Matsuoka, and G. W. Rebeck Fyn Modulation of Dab1 Effects on Amyloid Precursor Protein and ApoE Receptor 2 Processing J. Biol. Chem., March 7, 2008; 283(10): 6288 - 6299. [Abstract] [Full Text] [PDF]

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