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The Journal of Neuroscience, March 1, 2000, 20(5):1657-1665

Neurons Regulate Extracellular Levels of Amyloid -Protein via Proteolysis by Insulin-Degrading Enzyme

Konstantinos Vekrellis¹, Zhen Ye¹, Wei Qiao Qiu¹, Dominic Walsh¹, Dean Hartley¹, Valérie Chesneau², Marsha Rich Rosner², and Dennis J. Selkoe¹

¹ Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, and ² Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637

Progressive cerebral accumulation of amyloid -protein (A) is an early and invariant feature of Alzheimer's disease. Little is known about how A, after being secreted, is degraded and cleared from the extracellular space of the brain. Defective A degradation could be a risk factor for the development of Alzheimer's disease in some subjects. We reported previously that microglial cells release substantial amounts of an A-degrading protease that, after purification, is indistinguishable from insulin-degrading enzyme (IDE). Here we searched for and characterized a role for IDE in A degradation by neurons, the principal cell type that produces A. Whole cultures of differentiated pheochromocytoma (PC12) cells and primary rat cortical neurons actively degraded endogenously secreted A via IDE. However, unlike that in microglia, IDE in differentiated neurons was not released but localized to the cell surface, as demonstrated by biotinylation. Undifferentiated PC12 cells released IDE into their medium, whereas after differentiation, IDE was cell associated but still degraded A in the medium. Overexpression of IDE in mammalian cells markedly reduced the steady-state levels of extracellular A₄₀ and A₄₂, and the catalytic site mutation (E111Q) abolished this effect. We observed a novel membrane-associated form of IDE that is ~5 kDa larger than the known cytosolic form in a variety of cells, including differentiated PC12 cells. Our results support a principal role for membrane-associated and secreted IDE isoforms in the degradation and clearance of naturally secreted A by neurons and microglia.

Key words: neurons; Alzheimer's disease; amyloid -protein degradation; insulin-degrading enzyme; oligomerization; membrane proteins

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2051657-09$05.00/0

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