help button home button Am J Pathol ASIP MEMBERSHIP
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Farris, W.
Right arrow Articles by Selkoe, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Farris, W.
Right arrow Articles by Selkoe, D. J.
(American Journal of Pathology. 2004;164:1425-1434.)
© 2004 American Society for Investigative Pathology

Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid ß-Protein

Wesley Farris*, Stefan Mansourian*, Malcolm A. Leissring*, Elizabeth A. Eckman{dagger}, Lars Bertram{ddagger}, Christopher B. Eckman{dagger}, Rudolph E. Tanzi{ddagger} and Dennis J. Selkoe*

From the Department of Neurology,* Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, Massachusetts; the Department of Neurology,{ddagger} Genetics and Aging Research Unit, Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the Mayo Clinic Jacksonville,{dagger} Jacksonville, Florida

The causes of cerebral accumulation of amyloid ß-protein (Aß) in most cases of Alzheimer’s disease (AD) remain unknown. We recently found that homozygous deletion of the insulin-degrading enzyme (IDE) gene in mice results in an early and marked elevation of cerebral Aß. Both genetic linkage and allelic association in the IDE region of chromosome 10 have been reported in families with late-onset AD. For IDE to remain a valid candidate gene for late-onset AD on functional grounds, it must be shown that partial loss of function of IDE can still alter Aß degradation, but without causing early, severe elevation of brain Aß. Here, we show that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus (DM2) result in decreased catalytic efficiency and a significant ~15 to 30% deficit in the degradation of both insulin and Aß. Endogenously secreted Aß40 and Aß42 are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Aß in the brain up to age 14 months. We conclude that naturally occurring, partial loss-of-function mutations in IDE sufficient to cause DM2 also impair neuronal regulation of Aß levels, but the brain can apparently compensate for the partial deficit during the life span of the rat. Our findings have relevance for the emerging genetic evidence suggesting that IDE may be a late-onset AD-risk gene, and for the epidemiological relationships among hyperinsulinemia, DM2, and AD.




This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Neant-Fery, R. D. Garcia-Ordonez, T. P. Logan, D. J. Selkoe, L. Li, L. Reinstatler, and M. A. Leissring
Molecular basis for the thiol sensitivity of insulin-degrading enzyme
PNAS, July 15, 2008; 105(28): 9582 - 9587.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Ahuja, B. Schwer, S. Carobbio, D. Waltregny, B. J. North, V. Castronovo, P. Maechler, and E. Verdin
Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase
J. Biol. Chem., November 16, 2007; 282(46): 33583 - 33592.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
S. Vepsalainen, M. Parkinson, S. Helisalmi, A. Mannermaa, H. Soininen, R. E Tanzi, L. Bertram, and M. Hiltunen
Insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population
J. Med. Genet., September 1, 2007; 44(9): 606 - 608.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Im, M. Manolopoulou, E. Malito, Y. Shen, J. Zhao, M. Neant-Fery, C.-Y. Sun, S. C. Meredith, S. S. Sisodia, M. A. Leissring, et al.
Structure of Substrate-free Human Insulin-degrading Enzyme (IDE) and Biophysical Analysis of ATP-induced Conformational Switch of IDE
J. Biol. Chem., August 31, 2007; 282(35): 25453 - 25463.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
E. Zeggini, M. N. Weedon, C. M. Lindgren, T. M. Frayling, K. S. Elliott, H. Lango, N. J. Timpson, J. R. B. Perry, N. W. Rayner, R. M. Freathy, et al.
Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
Science, June 1, 2007; 316(5829): 1336 - 1341.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Kim, L. B. Hersh, M. A. Leissring, M. Ingelsson, T. Matsui, W. Farris, A. Lu, B. T. Hyman, D. J. Selkoe, L. Bertram, et al.
Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families
J. Biol. Chem., March 16, 2007; 282(11): 7825 - 7832.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
S. M. Clee and A. D. Attie
The Genetic Landscape of Type 2 Diabetes in Mice
Endocr. Rev., February 1, 2007; 28(1): 48 - 83.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
Z. Arvanitakis, J. A. Schneider, R. S. Wilson, Y. Li, S. E. Arnold, Z. Wang, and D. A. Bennett
Diabetes is related to cerebral infarction but not to AD pathology in older persons
Neurology, December 12, 2006; 67(11): 1960 - 1965.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
A. Akomolafe, A. Beiser, J. B. Meigs, R. Au, R. C. Green, L. A. Farrer, P. A. Wolf, and S. Seshadri
Diabetes Mellitus and Risk of Developing Alzheimer Disease: Results From the Framingham Study
Arch Neurol, November 1, 2006; 63(11): 1551 - 1555.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Kim, A. N. Lapham, C. G. K. Freedman, T. L. Reed, and W. K. Schmidt
Yeast as a Tractable Genetic System for Functional Studies of the Insulin-degrading Enzyme
J. Biol. Chem., July 29, 2005; 280(30): 27481 - 27490.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. S. Song, A. Daily, M. G. Fried, M. A. Juliano, L. Juliano, and L. B. Hersh
Mutation of Active Site Residues of Insulin-degrading Enzyme Alters Allosteric Interactions
J. Biol. Chem., May 6, 2005; 280(18): 17701 - 17706.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
A F Wright
Neurogenetics II: complex disorders
J. Neurol. Neurosurg. Psychiatry, May 1, 2005; 76(5): 623 - 631.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
L. Zhao, B. Teter, T. Morihara, G. P. Lim, S. S. Ambegaokar, O. J. Ubeda, S. A. Frautschy, and G. M. Cole
Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention
J. Neurosci., December 8, 2004; 24(49): 11120 - 11126.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
A. J. TURNER, L. FISK, and N. N. NALIVAEVA
Targeting Amyloid-Degrading Enzymes as Therapeutic Strategies in Neurodegeneration
Ann. N.Y. Acad. Sci., December 1, 2004; 1035(1): 1 - 20.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Ghiso, M. Shayo, M. Calero, D. Ng, Y. Tomidokoro, S. Gandy, A. Rostagno, and B. Frangione
Systemic Catabolism of Alzheimer's A{beta}40 and A{beta}42
J. Biol. Chem., October 29, 2004; 279(44): 45897 - 45908.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
J. A. Luchsinger, M.-X. Tang, S. Shea, and R. Mayeux
Hyperinsulinemia and risk of Alzheimer disease
Neurology, October 12, 2004; 63(7): 1187 - 1192.
[Abstract] [Full Text] [PDF]

Home page
 Sci Aging Knowl EnvironHome page
Papers of Note
Sci. Aging Knowl. Environ., March 31, 2004; 2004(13): nw12 - nw12.
[Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2004 by the American Society for Investigative Pathology.