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

Abstract

Progressive cerebral accumulation of amyloid beta-protein (Abeta) is an early and invariant feature of Alzheimer's disease. Little is known about how Abeta, after being secreted, is degraded and cleared from the extracellular space of the brain. Defective Abeta 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 Abeta-degrading protease that, after purification, is indistinguishable from insulin-degrading enzyme (IDE). Here we searched for and characterized a role for IDE in Abeta degradation by neurons, the principal cell type that produces Abeta. Whole cultures of differentiated pheochromocytoma (PC12) cells and primary rat cortical neurons actively degraded endogenously secreted Abeta 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 Abeta in the medium. Overexpression of IDE in mammalian cells markedly reduced the steady-state levels of extracellular Abeta(40) and Abeta(42), and the catalytic site mutation (E111Q) abolished this effect. We observed a novel membrane-associated form of IDE that is approximately 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 Abeta by neurons and microglia.

Isolation and structure elucidation of tumescenamides A and B, two peptides produced by Streptomyces tumescens YM23-260

“…This enzyme, a metalloprotease enzyme responsible for insulin degradation, had been shown to have a key role in b-amyloid (Ab) peptide degradation both in vitro and in vivo, and was selective for Ab monomer. [9][10][11] Thus, substances which induce the upregulation of IDE enzyme are expected to be promising drugs for the treatment of Alzheimer's disease. Compound 1 induced reporter gene expression under the control of the IDE promoter more than three times at a concentration of 100 mM.…”

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

“…IDE (insulin-degrading enzyme) is a major endogenous Ab degrading enzyme that mediates Ab clearance, and its levels and enzymatic activity are negatively correlated with the size of the amyloid plaques and AD pathology. 3 In AD brains, IDE is mainly detected in astrocytes, 4 and located in the cytosol and intracellular compartments such as mitochondria and peroxisomes. 5 However, it is also known to play a role in the extracellular milieu via the secretory pathway.…”

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

“…IDE is a 110 kDa zinc-requiring metalloproteinase located in the cytoplasm, cell membranes and some cell organelles (endosomes, peroxisomes and mitochondria) and is secreted into the extracellular space [6][7][8]. Insulin is the preferred substrate for IDE, but a large body of other substrates, including glucagon, atrial natriuretic peptide and β-amyloid peptide, were reported [6].…”