Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is characterized by amyloid β (Aβ) accumulation in the brain and is classified as familial early-onset (FAD) or sporadic late-onset (SAD). Evidences suggest that deficits in the brain expression of insulin degrading enzyme (IDE) and neprilysin (NEP), both proteases involved in amyloid degradation, may promote Aβ deposition in SAD. We studied by immunohistochemistry IDE and NEP cortical expression in SAD and FAD samples carrying the E280A presenilin-1 missense mutation. We showed that IDE, a soluble peptidase, is linked with aggregated Aβ40 isoform while NEP, a membrane-bound protease, negatively correlates with amyloid angiopathy and its expression in the senile plaques is independent of aggregated amyloid and restricted to SAD cases. NEP, but not IDE, is over-expressed in dystrophic neurites, both proteases are immunoreactive in activated astrocytes but not in microglia and IDE was the only one detected in astrocytes of white matter from FAD cases. Collectively, our results support the notion that gross conformational changes involved in the modification from “natively folded-active” to “aggregated-inactive” IDE and NEP may be a relevant pathogenic mechanism in SAD.

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

“…In other words, we found that Ab could be degraded by inducing IDE secretion from astrocytes via autophagy-based secretory pathway under AD conditions. In previous studies, IDE is expressed in several cell types in brain such as neurons and endothelial cells as well as astrocytes, 53,54 however, Dorfman et al 4 show that astrocytes are the main cell types for IDE in AD pathology. In addition, when neurons, astrocytes or endothelial cells were treated with Ab, we found that only astrocytes increased IDE secretion (Fig.…”

“…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.…”

Key Enzymes and Proteins in Amyloid-Beta Production and Clearance

“…These are all the enzymes and proteins that, either by directly cleaving A into less harmful peptides or making them more prone to proteolysis or less susceptible to aggregation through protein-protein interactions, will reduce the A load in vulnerable areas of the brain. Reduced degradation of A by proteases is generally accepted to enhance plaque pathology in AD brains, and may depend on several factors such as decreased mRNA expression or decreased protein levels or activity, either in the brain cortex, hippocampus or in brain microvessels; and post-translational modifications, such as oxidation and deposition of the enzymes in the diseased brain with consequent loss of its native structure and functionality (Dorfman et al, 2010.). IDE and NEP are well accepted as A degrading enzymes, but although few studies compare the relative contribution of each of these enzymes to the overall A load, NEP seems to be the major protease involved in A degradation.…”

“…IDE enzyme hydrolyses several peptide bonds of both A 40 and A 42, but is particularly efficient at hydrolysing the Lys28-Gly29 peptide bond followed by the Phe19-Phe20 and His14-Gln15 bonds of these substrates (Bora, et al 2010;Bora and Prabhakar 2010). IDE is expressed by cortical and subcortical neurons, and has been detected in the cytoplasm of the three major components of the vascular wall: endothelial cells, pericytes and smooth muscle cells (Dorfman, et al 2010;Gao, et al 2004). IDE is also expressed towards the apical surface of the choroid plexus tissue where its inhibition leads to disrupted metabolism of A and its concurrent accumulation at the blood-CSF barrier (Behl, et al 2009).…”

“…It is also expressed in the tunica media and endothelium of cortical and leptomeningeal blood vessels where it participates in the regulation of the vascular tone, and in pyramidal neurons. NEP is also involved in the regulation of neuropeptide signalling (Dorfman et al 2010;Miners, et al 2008b). NEP has been implicated in the degradation of A .…”