Disease relevance of IDE

• Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD [1].
• Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular Abeta amyloidoses [2].
• Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy [2].
• Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease [3].
• Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system [4].

Psychiatry related information on IDE

• Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid (Abeta) peptide implicated in Alzheimer's disease (AD) [5].
• This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer's. Copyright (c) 2006 S [6].

High impact information on IDE

• Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus [7].
• Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection [7].
• IDE increases proteasome and steroid hormone receptor activity, and this activation is reversed by insulin [8].
• Most evidence supports IDE as the primary degradative mechanism, but other systems (PDI, lysosomes, and other enzymes) undoubtedly contribute to insulin metabolism [8].
• Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD) [9].

Chemical compound and disease context of IDE

• A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2 [1].
• Furthermore, cysteine is adjacent to the glutamate residue (HXCEH) in human, rat, and Drosophila IDE, although it is not conserved in their close homologue, Escherichia coli protease III [10].
• These data show that nelfinavir inhibits IDE, decreases insulin's ability to inhibit protein degradation via the proteasome and provides another possible mechanism for the insulin resistance seen in protease inhibitor-treated HIV patients [11].
• Functions and expression of insulysin, an enzyme involved in the degradation of neurotoxic amyloid peptides and insulin, are usually impaired or reduced in Alzheimer's disease and diabetes [12].

Biological context of IDE

• RAF activity co-purified with a 110-kDa protein, the partial amino acid sequence of which shares 97.5% identity with insulin degrading enzyme (IDE), a metalloendoprotease implicated in the intracellular degradation of insulin [13].
• Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted [5].
• We here report IDE gene promoter region variants that are associated with AD in subjects without an epsilon4 allele [5].
• Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD [14].
• IDE is located on chromosome 10q23.3 close to a region of linkage for LOAD [15].

Anatomical context of IDE

• IDE was present in BV-2 cytosol, as expected, but was also released into the medium by intact, healthy cells [16].
• To confirm the extracellular occurrence of IDE in vivo, we identified intact IDE in human cerebrospinal fluid of both normal and Alzheimer subjects [16].
• Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood-brain barrier, express IDE and may respond to exposure to low levels of Abeta by upregulating its expression [17].
• Further, our evidence suggests that degradation by IDE occurs on the plasma membrane, as much of the IDE present in HCECs was biotin-labeled by a plasma membrane impermeable reagent [17].
• A peroxisomal location for insulin-degrading enzyme (IDE) has been defined by confocal immunofluorescence microscopy of stably transfected CHO cells overexpressing IDE and digitonin-permeabilization studies in normal nontransfected fibroblasts [18].

Associations of IDE with chemical compounds

• The interactions of AR and GR with IDE may have important implications for both insulin- and steroid-mediated signaling [13].
• We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance [19].
• Moreover, intracellular A beta in the detergent-insoluble fraction extracted with 70% formic acid or 6 M guanidine hydrochloride decreased markedly in the cells overexpressing IDE [20].
• To identify a downstream zinc ligand, we substituted a glutamine for glutamate at either Glu182 or Glu189, both of which are conserved in human, rat, and Drosophila IDE [21].
• The role of the cysteine in IDE catalysis and inhibitor sensitivity was examined by mutating Cys110 to glycine or serine [10].
• We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families [22].

Physical interactions of IDE

• CONCLUSIONS: We propose that prolonged HAART and aging may contribute to an overall increase in amyloid deposition, potentially mediated by inhibition of insulin degradation enzyme (IDE) or disruption of the axonal transport of the amyloid precursor protein [23].

Regulatory relationships of IDE

• These results raise the possibility that upregulation of IDE may promote the clearance of soluble Abeta in hereditary forms of Abeta diseases [24].
• Genetic variation in a haplotype block spanning IDE influences Alzheimer disease [25].
• We also describe the stable transfection of Chinese hamster ovary cells with a plasmid containing the IDE cDNA under the transcriptional control of the SR alpha promoter [26].
• The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations [27].

Other interactions of IDE

• Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain [28].
• The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD [28].
• In addition, many studies have identified a possible role of IDE in the degradation of amyloid beta-protein and the intracellular amyloid precursor protein (APP) domain released by gamma-secretase processing [15].
• Insulin-degrading enzyme and Alzheimer disease: a genetic association study in the Han Chinese [15].
• The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status [28].

Analytical, diagnostic and therapeutic context of IDE

• In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzyme-linked immunosorbent assay and Western blot [2].
• Subcellular fractionation, immunofluorescent confocal microscopy, and immunogold-electron microscopy reveal that the 15b-IDE protein occurs in both cytosol and mitochondria [29].
• Direct proteolysis of the leader peptide of prethiolase was confirmed by HPLC; degradation was inhibited by immunodepletion with an antibody to IDE [18].
• Western-blot analysis with monoclonal antibodies indicated the presence of both IDE and PDI in the cytosolic fraction of human and monkey liver [30].
• Surprisingly, IDE-mediated proteolysis of [(125)I]Abeta(1-40) in microglial cell-culture media was accompanied by the formation of (125)I-labelled peptides with higher apparent molecular masses, raising the possibility that the degradation products act as 'seeds' for Abeta oligomerization [31].

References