Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined whether ischemia-induced amyloidogenesis could be modulated by environmental "experience," and whether this modulation is associated with improved cognitive functioning. Rats were subjected to either global ischemia or sham surgery and then were randomly assigned to either enriched environment housing (EE) or socially paired housing (controls). After 14 days of differential environmental housing, the rats were tested in the water maze. Our results show decreased C-terminal fragments of the beta-amyloid precursor protein (betaAPP) and decreased amyloid beta (Abeta) load in the ischemic EE rats compared to the ischemic control animals. In addition, Abeta oligomerization was significantly decreased in the ischemic EE animals compared to the ischemic control rats. Further, significantly increased levels of neprilysin, but not insulin-degrading enzyme, amyloid-degrading enzymes, were seen in the ischemic EE rats compared to the ischemic control animals. Behavioral analyses showed that ischemic EE rats performed significantly better on the memory task compared to the ischemic control group. These results suggest that use of multi-sensory environmental enrichment following cerebral ischemia may reduce the accumulation of Abeta peptide in the more pathologic oligomeric form, and consequently may enhance functional recovery.
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PMID:Environmental experience modulates ischemia-induced amyloidogenesis and enhances functional recovery. 2773 69

Experimental reduction of neprilysin (NEP) or insulin-degrading enzyme (IDE) in vivo exacerbates beta-amyloid accumulation in the brain. The level of these enzymes is reportedly reduced during aging and in postmortem brains of patients with sporadic Alzheimer disease (AD). To distinguish between primary decreases in NEP and IDE activity that might contribute to beta-amyloid accumulation and decreases secondary to neurodegenerative changes in AD, we measured NEP and IDE levels by indirect sandwich ELISA and enzyme activities by immunocapture-based fluorogenic assays in postmortem frontal cortex from patients of different ages and at different pathological stages of AD, as indicated by Braak tangle stage. The ELISA measurements of neuron-specific enolase were used to adjust for neuronal loss. Both unadjusted and neuron-specific enolase-adjusted NEP levels and activity were significantly increased in AD and positively correlated with Braak stage but negatively with age in AD patients. Insulin-degrading enzyme activity was higher in AD than controls; this was significant after adjustment for neuron-specific enolase level; unadjusted IDE protein level was decreased in AD but not after adjustment. Our findings suggest that reduction in NEP and IDE activity is not the primary cause of beta-amyloid accumulation in AD, but rather a late-stage phenomenon secondary to neurodegeneration.
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PMID:Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. 1960 63

The significance of intracellular beta-amyloid (Abeta(42)) accumulation is increasingly recognized in Alzheimer's disease (AD) pathogenesis. Abeta removal mechanisms that have attracted attention include IDE/neprilysin degradation and antibody-mediated uptake by immune cells. However, the role of the ubiquitin-proteasome system (UPS) in the disposal of cellular Abeta has not been fully explored. The E3 ubiquitin ligase Parkin targets several proteins for UPS degradation, and Parkin mutations are the major cause of autosomal recessive Parkinson's disease. We tested whether Parkin has cross-function to target misfolded proteins in AD for proteasome-dependent clearance in SH-SY5Y and primary neuronal cells. Wild-type Parkin greatly decreased steady-state levels of intracellular Abeta(42), an action abrogated by proteasome inhibitors. Intracellular Abeta(42) accumulation decreased cell viability and proteasome activity. Accordingly, Parkin reversed both effects. Changes in mitochondrial ATP production from Abeta or Parkin did not account for their effects on the proteasome. Parkin knock-down led to accumulation of Abeta. In AD brain, Parkin was found to interact with Abeta and its levels were reduced. Thus, Parkin is cytoprotective, partially by increasing the removal of cellular Abeta through a proteasome-dependent pathway.
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PMID:Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function. 1961 Jan 8

Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation, and efflux of Abeta in the mice. The clearance of intracerebral-microinjected (125)I-Abeta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa(-/-)APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in Abeta transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa(-/-) mouse brains. Moreover, the disappearance of intravenously administered (125)I-Abeta(1-40) was decreased in Ttpa(-/-) mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-tocopherol impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa(-/-)APPsw mouse brain and plasma.
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PMID:Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. 1967 59

The metabolism of the amyloid precursor protein (APP) and tau are central to the pathobiology of Alzheimer's disease (AD). We have examined the in vivo turnover of APP, secreted APP (sAPP), Abeta and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Abeta degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Abeta40 and Abeta42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a beta-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the beta-amyloid depositing Tg2576 mice may represent a neuroprotective response.
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PMID:In vivo turnover of tau and APP metabolites in the brains of wild-type and Tg2576 mice: greater stability of sAPP in the beta-amyloid depositing mice. 1977 Nov 66

Polymorphisms in genes encoding amyloid beta-peptide (A beta)-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) individually affect the susceptibility to Alzheimer disease (AD) among the Finnish population. Here we show that a combination of risk genotypes for NEP and IDE genes leads to a higher susceptibility to AD. Individuals with the combination of risk genotypes for NEP and IDE conferred a threefold higher susceptibility to AD when compared with individuals not carrying these genotypes. Although no significant interaction was observed between NEP and IDE genes, these data suggest that NEP and IDE exhibit an additive risk effect in AD.
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PMID:Combined risk effects of IDE and NEP gene variants on Alzheimer disease. 1986 59

Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn(2+) -dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid beta peptide (Abeta) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-alpha, beta-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate beta strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.
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PMID:Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease. 1992 17

Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer's disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy). In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype. Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Abeta levels in the cortex and hippocampus, and an elevation of Abeta deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Abeta catabolic pathways, i.e. IDE and neprilysin proteins, or the Abeta chaperone apolipoprotein E. Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Abeta levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.
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PMID:Acceleration of brain amyloidosis in an Alzheimer's disease mouse model by a folate, vitamin B6 and B12-deficient diet. 2000 83

We recently found that insoluble Abeta increases, but soluble Abeta decreases with age in normal brains. We now report the changes in activities of beta-secretase (BACE-1) and Abeta-degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Abeta. We measured BACE-1 activity and the levels and activities of neprilysin (NEP), insulin-degrading enzyme (IDE) and angiotensin-converting enzyme (ACE) in normal control brains (16 years-95 years). We also compared the measurements to those in AD. BACE-1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE-1 activity correlated directly with insoluble but inversely with soluble Abeta. IDE activity correlated directly with insoluble Abeta and NEP activity was inversely related to soluble Abeta. ACE level correlated directly with insoluble and inversely with soluble Abeta in controls but not AD. Both Abeta-synthesizing and -degrading enzyme activities increase with age, coinciding with declining soluble Abeta and increasing insoluble Abeta. Further research is needed to establish whether these changes in enzyme activity and Abeta levels are causally related and if so how.
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PMID:Changes with age in the activities of beta-secretase and the Abeta-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. 2017 76

Amyloid beta (Abeta) fibrils are found in the brain tissue of persons with Alzheimer's disease (AD), where they accumulate as plaques. One way to reduce the level of accumulation of Abeta in the brain and potentially treat AD is with Abeta-degrading enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, enzymatic responses and degradation mechanisms of Abeta fibrils (crystalline-state Abeta) have not been investigated, particularly with respect to how to avoid cytotoxicity of the degradation products to neuronal cells. Thus, insight into mechanisms of enzymatic degradation of Abeta fibrils would be instructive as a route to elucidating different structural features related to degradation and to cytotoxicity. We report mechanisms of enzymatic degradation of Abeta with cross-beta structures and show the series of steps involved in the digestion of Abeta microfibrils to nanospheres or nanofilaments by protease XIV or alpha-chymotrypsin, respectively. These degradation products, which contained almost the same secondary structures, exhibited different cytotoxicities, indicating that relationships between nanoassembled structures and cytotoxicity of Abeta peptides are more significant than the beta-sheet content. In addition, the enzymatic digestion at the Lys28 loop region linking the two beta-sheets in Abeta fibrils is suggested as a key target related to cytotoxicity, a feature that can be selectively targeted on the basis of the choice of protease.
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PMID:Mechanisms of enzymatic degradation of amyloid Beta microfibrils generating nanofilaments and nanospheres related to cytotoxicity. 2019 18


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