Abstract
Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the β-amyloid (Aβ) peptide implicated in Alzheimer’s disease (AD). Hence, factors that influence IDE expression or IDE activity toward Aβ are potentially relevant to the etiology of AD. Hippocampal IDE mRNA levels are lower on average in subjects with an APOE ε4 allele, suggesting that the genetic risk conferred by APOE ε4 may be mediated in part by this allele’ effect on IDE expression. Other factors that influence IDE may be relevant in non-ε4 carriers. For example, insulin, a competitive inhibitor of IDE activity toward Aβ, may be elevated in non-ε4 cases. We here report IDE gene promoter region variants that are associated with AD in subjects without an ε4 allele. If these promoter region variants prove to affect expression levels, they may be relevant to disease as well. Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abraham R., Myers A., Wavrant-DeVrieze F., Hamshere M. L., Thomas H. V., Marshall H., et al. (2001) Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer’s disease. Hum. Genet. 109, 646–652.
Ait-Ghezala G., Abdullah L., Crestentini R., Crawford F., Town T., Singh S., et al. (2002) Confirmation of association between D10S583 and Alzheimer’s disease in a case-control sample. Neurosci. Lett. 325, 87–90.
Bertram L., Blacker D., Mullin K., Keeney D., Jones J., Basu S., et al. (2000) Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 290, 2302,2303.
Boussaha M., Hannequin D., Verpillat P., Brice A., Frebourg T., and Campion D. (2002) Polymorphisms of insulin degrading enzyme gene are not associated with Alzheimer’s disease. Neurosci. Lett. 329, 121–123.
Cook D. G., Leverenz J. B., McMillan P. J., Kulstad J. J., Ericksen S., Roth R. A., et al. (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-ε4 allele. Am. J. Pathol. 162, 313–319.
Graft S., Asthana S., Schellenberg G., Cherrier M., Baker L. D., Newcomer J., et al. (1999) Insulin metabolism in Alzheimer’s disease differs according to apolipoprotein Egenotype and gender. Neuroendocrinology 70, 146–152.
Eckman E.A., Reed D.K., and Eckman C.B. (2001) Degradation of Alzheimer’s amyloid β peptide by endothelin-converting enzyme. J. Biol. Chem. 276, 24540–24548.
Edland S. D., Wavrant-DeVrieze F., Compton D., Smith G. E., Ivnik R., Boeve B. F., et al. (2002), “Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer’s disease: evidence of effect modification by APOE.” Abstract Viewer/Itinerary Planner, Society for Neuroscience, Washington, D. C., Online Program no. 785.3.
Edland S. D., Wavrant-DeVrieze F., Compton D., Smith G. E., Ivnik R., Boeve B. F., et al. (2003) Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer’s disease: evidence of effect modification by apolipoprotein E (APOE). Neurosci. Lett. 345, 21–24.
Edland S. D., Slager S., and Farrer M. (2004) Genetic association studies in Alzheimer’s disease research: challenges and opportunities. Stat. Med. 23, 169–178.
Ertekin-Taner N., Graff-Radford N., Younkin L. H., Eckman C., Baker M., Adamson J., et al. (2000) Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 290, 2303, 2304.
Farris W., Mansourian S., Chang Y., Lindsley. L., Eckman E. A., Frosch M. P., et al. (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid β protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. USA 100, 4162–4167.
Kulstad J. J., Leverenz J., McMillan P., Peskind E. R., Cook, D. G., and Craft S. (2000) “Chronicglucocorticoid administration reduces insulin degrading enzyme levels in frontal cortex and hippocampus in the aged macque.” Abstract Viewer/Itinerary Planner, Society for Neuroscience, Washington, D. C., Online Program no. 688.19.
Kurochkin I. V. and Goto S. (1994). Alzheimer’s β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 345, 33–37.
Kuusisto J., Koivisto K., Mykkanen L., Helkala E. L., Vanhanen M., Hanninen T., et al. (1997) Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein E4 phenotype: cross sectional population based study. Br. Med J. 315, 1045–1049.
Myers A., Holmans P., Marshall H., Kwon J., Meyer D., Ramic D., et al. 2000. Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 290, 2304,2305.
Perez A., Morelli L., Cresto J. C., and Castano E. M. (2000) Degradation of soluble amyloid β-peptides 1–40, 1–42, and the Dutch variant 1–40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem. Res. 25, 247–255.
Peskind E. R., Wilkinson C. W., Petrie E. C., Schellenberg G. D., and Raskind M. A. (2001) Increased CSF cortisol in AD is a function of APOE genotype. Neurology 56, 1094–1098.
Selkoe D. J. 2001. Clearing the brain’s amyloid cobwebs. Neuron 32, 177–180.
Vekrellis K., Ye Z., Qiu W. Q., Walsh D., Hartley D., Chesneau V., et al. (2000) Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657–1665.
Yan Y., Yuan W., Velculescu V. E., Vogelstein B., and Kinzler K. W. (2002) Allelic variation in human gene expression. Science 297, 1143.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Edland, S.D. Insulin-degrading enzyme, apolipoprotein E, and Alzheimer’s disease. J Mol Neurosci 23, 213–217 (2004). https://doi.org/10.1385/JMN:23:3:213
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:23:3:213