Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic Tg2576 mice with Alzheimer pathology

Abstract

It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid β (Aβ) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Aβ precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Aβ and massive Aβ deposition into plaques. At this stage, IDE appeared surrounding Aβ fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Aβ-mediated inflammation process. When primary astrocytes were exposed to fibrillar Aβ in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Aβ-triggered inflammation. © 2006 American Association of Neuropathologists, Inc.