. Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol. 2004 Apr;164(4):1425-34. PubMed.

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  1. As reported by Schmitz et al., IDE may be involved in degradation of Aβ transported from the inside of the ER to the cytoplasm, particularly under pathological conditions (1). However, I would urge caution in directly relating IDE mutations with AD through Aβ degradation for the following reasons. [1] Insulin and AICD (and quite likely some cytosolic peptides similar to AICD) are far better substrates than Aβ for IDE. [2] Insulin is known to alter APP processing through a distinct signal transduction mechanism (2,3). Therefore, it is very likely that the relationship between diabetes and AD can be accounted for primarily by altered insulin signaling.

    References:

    . Endoplasmic reticulum-localized amyloid beta-peptide is degraded in the cytosol by two distinct degradation pathways. Traffic. 2004 Feb;5(2):89-101. PubMed.

    . Insulin-regulated β-amyloid protein trafficking: Stimulated secretion and reduced intracellular accumulation of Aβ in neuronal cell cultures. Neurobiology of Aging, May 2000, vol. 21, no. 1001, pp. 183-183(1).

    . Does insulin dysfunction play a role in Alzheimer's disease?. Trends Pharmacol Sci. 2002 Jun;23(6):288-93. PubMed.

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