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J. Biol. Chem., Vol. 282, Issue 11, 7825-7832, March 16, 2007

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Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families^*

Minji Kim, Louis B. Hersh, Malcolm A. Leissring^¶, Martin Ingelsson^||, Toshifumi Matsui^||, Wesley Farris^¶, Alice Lu, Bradley T. Hyman^||, Dennis J. Selkoe^¶, Lars Bertram, and Rudolph E. Tanzi¹

From the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, ^¶Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, and ^||Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that degrades the amyloid -peptide, the key component of Alzheimer disease (AD)-associated senile plaques. We have previously reported evidence for genetic linkage and association of AD on chromosome 10q23–24 in the region harboring the IDE gene. Here we have presented the first functional assessment of IDE in AD families showing the strongest evidence of the genetic linkage. We have examined the catalytic activity and expression of IDE in lymphoblast samples from 12 affected and unaffected members of three chromosome 10-linked AD pedigrees in the National Institute of Mental Health AD Genetics Initiative family sample. We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families. Further, we have shown the decrease in activity is not due to reduced IDE expression, suggesting the possible defects in IDE function in these AD families. In attempts to find potential mutations in the IDE gene in these families, we have found no coding region substitutions or alterations in splicing of the canonical exons and exon 15b of IDE. We have also found that total IDE mRNA levels are not significantly different in sporadic AD versus age-matched control brains. Collectively, our data suggest that the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression, further supporting a role for IDE in AD pathogenesis.

Received for publication, September 27, 2006 , and in revised form, January 22, 2007.

^* This work was supported by grants from the National Institute of Mental Health, National Institute on Drug Abuse, NIA, National Institutes of Health, Cure Alzheimer Fund, the John Douglas French Foundation, and the Swedish Research Council. 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.

¹ To whom correspondence should be addressed: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Bldg. 114, 16th St. C3009, Charlestown, MA 02129-4404. Tel.: 617-726-6845; Fax: 617-724-1949; E-mail: tanzi{at}helix.mgh.harvard.edu.

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