Insulin-degrading enzyme (IDE) plays a role in breaking down Aβ outside of neurons, report Dennis Selkoe, Konstantinos Vekrellis, and their colleagues at Harvard in the March 1 issue of the Journal of Neuroscience. The finding highlights growing interest in biological mechanisms that remove Aβ deposits, a topic that had once been overlooked because aggregated Aβ is virtually impervious to breaking down in the test tube. But growing evidence indicates the existence of processes that degrade Aβ deposits and the notion that these processes may also play an important role in pathogenesis and may offer good targets for drug therapy.
Selkoe's group followed up on their previous work, which had shown that cultured microglia use IDE as their main Aβ-degrading enzyme, byfinding that the same is true for cultured pheochromocytoma (PC12) cells and primary rat cortical neurons. The difference for neurons, they report, is that the IDE was localized to the cell surface of neurons, rather than released into the extracellular space. Overexpression of IDE markedly reduced extracellular levels of Aβ40 and Aβ42, and inactivation of IDE at its catalytic site eliminated this Aβ reduction. The researchers also found that the membrane-bound IDE appears to be a novel form slightly different in structure from the usual dissolved form.
Although these data suggest experiments to look for IDE gene changes in Alzheimer's populations and might open up a new route to therapy, Selkoe doesn't think that the results bear on the question of a link between Alzheimer's and diabetes. "It's simply too early to tell whether our fingering IDE as an Aβ-degrading protease in the nervous system means that patients with high circulating levels of insulin (e.g., insulin-resistant diabetics or diabetics treated with insulin) would have more of their IDE activity taken up by the insulin and therefore accumulate more Aβ in their brains," Selkoe told the Alzheimer Research Forum.—Hakon Heimer
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- Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000 Mar 1;20(5):1657-65. PubMed.