Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein
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The causes of cerebral accumulation of amyloid beta-protein (Abeta) 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 Abeta. 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 Abeta degradation, but without causing early, severe elevation of brain Abeta. 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 approximately 15 to 30% deficit in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and Abeta(42) are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Abeta 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 Abeta 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.
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IDE is a strong biological candidate because of postulated effects on insulin signalling and islet function and rodent model data.
“IDE represents a second strong biological candidate given postulated effects on both insulin signalling and islet function, and data from rodent models (15-17).”
From Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes (2007) · cites this paper as [17]
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Kurochkin, I. V., Guarnera, E., & Berezovsky, I. N. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.10.008 · Cited by 185 · see citing works
Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin
Malito, E., Hulse, R. E., & Tang, W.-J. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8112-4 · Cited by 176 · see citing works
Campos-Peña, V., Toral-Rios, D., Becerril-Pérez, F., Sánchez-Torres, C., Delgado-Namorado, Y., Torres-Ossorio, E., Franco-Bocanegra, D., & Carvajal, K. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6768 · Cited by 58 · see citing works
Use of Genetic Variation as Biomarkers for Alzheimer's Disease
Reitz, C., & Mayeux, R. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04945.x · Cited by 24 · see citing works
Ansari, P., Khan, J. T., Choudhary, S., Reberio, A. D., Kumar, S., Seidel, V., Abdel-Wahab, Y. H. A., & Flatt, P. R. (2024) · doi:10.20944/preprints202408.1739.v1 · Cited by 89 · see citing works
- Authors
- Farris, W., Mansourian, S., Leissring, M. A., Eckman, E. A., Bertram, L., Eckman, C. B., Tanzi, R. E., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Mayo Clinic (US)
- Harvard University (US)
- Corresponding author
- Selkoe, Dennis J.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 164
- Issue
- 4
- Pages
- 1425-1434
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1615329
- OpenAlex
- W1988531009
- Cited by
- 269
- References
- 66
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 6 · 2022: 15 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 11 · 2014: 9 · 2013: 12 · 2012: 15
- FWCI
- 15.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG12479)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- insulin-degrading enzyme, amyloid-beta, Alzheimer's disease, type 2 diabetes, missense mutations, amyloid beta degradation, insulin degradation, hyperinsulinemia
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Cricetulus, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Cricetinae, Humans, Insulin, Insulysin, Neurons, Transfection, Immunoblotting, Amyloid beta-Peptides, CHO Cells, Mutation, Missense, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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