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Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
Abstract
Two substrates of insulin-degrading enzyme (IDE), amyloid β-protein (Aβ) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Aβ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Aβ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE −/−). IDE deficiency resulted in a >50% decrease in Aβ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE −/− mice showed increased cerebral accumulation of endogenous Aβ, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the β-amyloid precursor protein, which was recently found to be degraded by IDE in vitro . Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
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“A is cleared from the brain via several clearance mechanisms, such as uptake and degradation by astro- cytes and microglia, 7,8 via A-degrading enzymes, such as neprilysin, endothelin-converting enzyme, and insulindegrading enzyme, 40 -42 and via transport by cerebral cells across the blood-brain barrier into the blood.”
From Lipoprotein Receptor-Related Protein-1 Mediates Amyloid-β-Mediated Cell Death of Cerebrovascular Cells (2007) · cites this paper as [41]
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Metadata
- Authors
- Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., & Guénette, S.
- Affiliations
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115; Harvard Medical School, Boston, MA 02115; Center for Aging, Genetics, and Neurodegeneration, Department of Neurology, Massachusetts General Hospital, Boston, MA 02129; and Mayo Clinic, Jacksonville, FL 32224
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-03-12
- Volume
- 100
- Issue
- 7
- Pages
- 4162-4167
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 1,286
- References
- 8
- Language
- en
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