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The Journal of Neuroscience, December 31, 2008, 28(53):14392-14400; doi:10.1523/JNEUROSCI.2481-08.2008

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Neurobiology of Disease
Deletion of Mint Proteins Decreases Amyloid Production in Transgenic Mouse Models of Alzheimer's Disease

Angela Ho,¹ Xinran Liu,¹ and Thomas C. Südhof^1,2,3

Departments of ¹Neuroscience and ²Molecular Genetics, and ³Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111

Correspondence should be addressed to either of the following at their present addresses: Angela Ho, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, Email: aho1{at}bu.edu; or Thomas C. Südhof, Institutes of Medicine, Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, E-mail: Email: tcs1{at}stanford.edu

Mints/X11s are neuronal adaptor proteins that bind to amyloid-β precursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage and affect production of pathogenic amyloid-β (Aβ) peptides in Alzheimer's disease; however, the biological significance of Mint/X11 binding to APP and their possible role in Aβ production remain unclear. Here, we crossed conditional and constitutive Mint1, Mint2, and Mint3 knock-out mice with transgenic mouse models of Alzheimer's disease overproducing human Aβ peptides. We show that deletion of all three individual Mint proteins delays the age-dependent production of amyloid plaque numbers and Aβ40 and Aβ42 levels with loss of Mint2 having the largest effect. Acute conditional deletion of all three Mints in cultured neurons suppresses the accumulation of APP C-terminal fragments and the secretion of ectodomain APP by decreasing β-cleavage but does not impair subsequent -cleavage. These results suggest that the three Mint/X11 proteins regulate Aβ production by a novel mechanism that may have implications for therapeutic approaches to altering APP cleavage in Alzheimer's disease.

Key words: Mint; X11; APP; β-amyloid; Alzheimer's disease; knock-out

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Received June 2, 2008; revised Oct. 15, 2008; accepted Nov. 18, 2008.

Correspondence should be addressed to either of the following at their present addresses: Angela Ho, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, Email: aho1{at}bu.edu; or Thomas C. Südhof, Institutes of Medicine, Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, E-mail: Email: tcs1{at}stanford.edu

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