Affinage

IDE

Insulin-degrading enzyme · UniProt P14735

Length
1019 aa
Mass
118.0 kDa
Annotated
2026-06-10
100 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IDE is a zinc metalloprotease that degrades insulin, amyloid-β (Aβ), and other peptide substrates through a dimer-dependent allosteric mechanism in which a rate-limiting conformational switch between a closed (inactive) and open (active) state governs catalysis (PMID:17613531). Crystallographic and biophysical analysis established that substrate-free IDE rests in the closed state, that destabilizing the IDE-N/IDE-C interface accelerates Aβ turnover by increasing Vmax, and that ATP facilitates the closed-to-open transition (PMID:17613531); deletion of the C-terminal dimer interface abolishes allosteric (sigmoidal) kinetics and the ability of small activators to stimulate large-substrate degradation, demonstrating that oligomerization is required for IDE's regulatory behavior (PMID:20300529). Efficient degradation of extracellular Aβ and insulin depends on a membrane-associated IDE pool localized to detergent-resistant membrane microdomains, the integrity of which is cholesterol-dependent (PMID:19117523). IDE expression is tightly controlled at the transcriptional level: the Notch effectors HES-1 and Hey-1 bind the IDE proximal promoter and repress its transcription and activity, linking Notch signaling to Aβ metabolism in vivo (PMID:22036964), a functional promoter variant (rs6583817) raises IDE transcript levels and associates with lower plasma Aβ40 and reduced late-onset Alzheimer's disease risk (PMID:20098734), and ApoE4 lowers neuronal IDE through an NMDA-receptor/PKA pathway (PMID:19616072). Beyond Aβ clearance, IDE controls β-cell function by degrading α-synuclein to sustain autophagic flux and glucose-stimulated insulin secretion (PMID:23349488), mediates SIRT4-bridged lysosomal degradation of PTEN under nutritional stress (PMID:30649986), and is positively regulated by SNX5 to control renal insulin handling (PMID:29080975). IDE additionally has a non-enzymatic role in shaping microglial phenotype in the hippocampus (PMID:37817156).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Establishing how IDE catalysis is regulated, the closed crystal structure plus interface mutagenesis showed the closed-to-open conformational switch is the rate-limiting step and that ATP promotes opening.

    Evidence X-ray crystallography of substrate-free IDE, interface mutagenesis with in vitro kinetics, and biophysical analysis of ATP-induced conformational change

    PMID:17613531

    Open questions at the time
    • Did not resolve a substrate-bound open-state structure
    • Physiological trigger that promotes opening in cells not defined
  2. 2008 High

    Resolving where active IDE operates, endogenous IDE was shown to partition between cytosol and cholesterol-dependent detergent-resistant membranes required for efficient Aβ and insulin degradation.

    Evidence Live immunofluorescence, immuno-gold EM, density-gradient fractionation, MβCD cholesterol depletion, and seladin-1 KO mice with degradation assays

    PMID:19117523

    Open questions at the time
    • Mechanism of IDE targeting to DRMs unknown
    • No membrane-anchoring partner identified
  3. 2010 High

    Testing whether oligomerization underlies allosteric regulation, a monomeric IDE variant retained basal activity but lost sigmoidal kinetics and activator responsiveness, proving the dimer interface is required for regulation.

    Evidence Dimer-interface deletion mutagenesis, size-exclusion chromatography, and kinetic/activator assays across multiple substrates

    PMID:20300529

    Open questions at the time
    • Endogenous oligomeric state in cells not quantified
    • Physiological allosteric activators not identified
  4. 2009 Medium

    Connecting an Alzheimer's risk factor to IDE, ApoE4 was shown to repress neuronal IDE via an LDL-receptor-family/NMDA-receptor/PKA pathway.

    Evidence ApoE isoform treatment of primary hippocampal neurons with NMDA-receptor and PKA pharmacology, RAP blockade, and IDE western blotting

    PMID:19616072

    Open questions at the time
    • Transcription factor executing PKA-dependent repression not identified
    • Pharmacology not confirmed with genetic perturbation
  5. 2010 Medium

    Linking IDE expression level to disease risk, a functional promoter SNP (rs6583817) was shown to raise IDE transcription and associate with lower plasma Aβ40 and reduced LOAD risk.

    Evidence Dual luciferase reporter assays, cerebellar eQTL analysis, GWAS proxy for plasma Aβ40, and case-control association

    PMID:20098734

    Open questions at the time
    • Transcription factor binding the variant not identified
    • Causal contribution to brain Aβ not directly shown
  6. 2011 High

    Defining a transcriptional repressor of IDE, Notch effectors HES-1/Hey-1 were shown to bind the IDE promoter and repress its expression, coupling Notch signaling to Aβ accumulation.

    Evidence Promoter luciferase reporter with site-directed mutagenesis, NICD/HES-1/Hey-1 transfection, qRT-PCR, and JAG-1 intracranial injection in Tg2576 mice

    PMID:22036964

    Open questions at the time
    • Direct promoter occupancy not shown by ChIP
    • Interplay with other IDE regulators not addressed
  7. 2011 Medium

    Identifying a regulator of extracellular IDE, BRI2 (ITM2B) overexpression was shown to increase secreted IDE and lower extracellular Aβ.

    Evidence BRI2/ADanPP and truncation construct overexpression, conditioned-medium Aβ and IDE ELISA/western, and AD mouse plaque assessment

    PMID:21873424

    Open questions at the time
    • Direct BRI2-IDE binding not resolved
    • Mechanism of IDE secretion not defined
  8. 2012 Medium

    Probing a proteostasis role, stress-inducible IDE was found to associate with proteasome components and ubiquitin and to be required for cell survival and poly-ubiquitinated protein levels.

    Evidence Stress-induction analysis, siRNA knockdown viability assays, and co-IP of IDE with proteasome/ubiquitin in SH-SY5Y cells

    PMID:23188819

    Open questions at the time
    • Direct enzymatic substrate in this pathway not identified
    • Co-IP not reciprocally validated
  9. 2013 High

    Establishing IDE's role in β-cell physiology, Ide-KO mice showed impaired glucose-stimulated insulin secretion via accumulation of α-synuclein and reduced autophagic flux.

    Evidence Ide KO/haploinsufficient mice, in vivo GSIS and autophagy assays, and α-synuclein gain/loss-of-function transgenic models

    PMID:23349488

    Open questions at the time
    • Whether IDE degrades α-synuclein directly in β-cells not biochemically isolated
    • Link between autophagy defect and granule pool not fully mechanistic
  10. 2017 High

    Identifying a positive regulator, SNX5 was shown to co-localize with and bind IDE and to maintain renal IDE expression/activity controlling insulin handling.

    Evidence Co-immunofluorescence, reciprocal co-IP, siRNA knockdown in hRPTCs, and renal-selective Snx5 silencing in mice with metabolic phenotyping

    PMID:29080975

    Open questions at the time
    • Mechanism by which SNX5 stabilizes IDE not defined
    • Generalization beyond kidney not established
  11. 2019 Medium

    Extending IDE to a new substrate pathway, SIRT4 was shown to bridge PTEN to IDE for lysosomal degradation under nutritional stress.

    Evidence Reciprocal co-IP of SIRT4/PTEN/IDE, SIRT4 overexpression with PTEN quantification, IDE inhibition rescue, and lysosomal pathway inhibitors

    PMID:30649986

    Open questions at the time
    • Direct IDE-mediated PTEN cleavage not reconstituted
    • How cytosolic/membrane IDE accesses lysosomal substrate unclear
  12. 2023 Medium

    Revealing a non-proteolytic function, IDE-KO mice exhibited hippocampal microgliosis and impaired microglial phenotype modulation not explained by Aβ degradation.

    Evidence IDE-KO mouse immunohistochemistry, behavioral testing, and primary microglial cultures with functional phenotyping

    PMID:37817156

    Open questions at the time
    • Molecular basis of the non-enzymatic microglial role unknown
    • Relevant IDE-binding partner in microglia not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IDE's catalytic conformational cycle, membrane localization, and diverse transcriptional/post-translational regulators are integrated to direct substrate choice across insulin, Aβ, α-synuclein, and PTEN remains unresolved.
  • No unified model linking allosteric state to substrate selectivity in vivo
  • Determinants of cytosolic vs membrane vs lysosomal substrate access unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
ITM2BPTENSIRT4SNX5

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Crystal structure of substrate-free human IDE in closed conformation reveals the molecular details of the active catalytic site and how the closed conformation keeps IDE in a resting, inactive state. Destabilizing mutations at the IDE-N/IDE-C interface (D426C and K899C) increase Vmax for Aβ degradation with minimal Km change, demonstrating that the conformational switch from closed to open is rate-limiting. ATP was shown to induce an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure, supporting a mechanism whereby ATP facilitates the transition from closed to open conformation. X-ray crystallography of substrate-free IDE; active-site interface mutagenesis with in vitro kinetic assays; biophysical analysis (dynamic light scattering, native PAGE, CD spectroscopy) of ATP-induced conformational change The Journal of biological chemistry High 17613531
2010 Deletion of the dimer interface in the C-terminal region of IDE yields a monomeric variant that retains enzymatic activity but displays Michaelis-Menten (non-allosteric) kinetics instead of the sigmoidal allosteric behavior of wild-type IDE. Monomeric IDE retains ~25% activity on a small fluorescent peptide substrate but only 0.25–1% of wild-type activity on large peptide substrates (β-endorphin, Aβ1-40). Neither bradykinin, dynorphin B-9, nor polyphosphates activate monomeric IDE, establishing that oligomerization (dimer interface) is required for IDE's regulatory/allosteric properties and that activator binding induces a conformational change that cannot occur in the monomer. Site-directed mutagenesis to delete dimer interface; size-exclusion chromatography to confirm monomer; in vitro kinetic assays with multiple substrates; activator dose-response assays PloS one High 20300529
2008 Endogenous IDE from brain tissue and cultured cells associates with detergent-resistant membranes (DRMs/lipid rafts) in addition to cytosolic localization. Live immunofluorescence, immuno-gold electron microscopy, and gradient fractionation demonstrate two IDE pools: cytosolic (longer half-life) and membrane-associated (faster turnover). Disruption of DRM integrity by methyl-β-cyclodextrin (MβCD) mislocalizes IDE away from DRMs, causing extracellular Aβ accumulation and impairing both exogenous Aβ and insulin degradation. Reduction of cholesterol in vivo (seladin-1 heterozygous knockout mice) also reduces DRM-associated IDE and diminishes IDE-mediated substrate degradation. Live immunofluorescence; immuno-gold electron microscopy; sucrose density gradient fractionation; pulse-chase turnover assays; MβCD-mediated cholesterol depletion; seladin-1 KO mouse model; in vitro Aβ/insulin degradation assays Molecular neurodegeneration High 19117523
2011 Notch target transcription factors HES-1 and Hey-1 directly bind to two functional sites in the IDE proximal promoter (at positions −379/−372 and −310/−303 from the first translation start site) and repress IDE transcription and enzymatic activity. Transient transfection of Notch intracellular domain (NICD) in N2aSW neuroblastoma cells reduces IDE mRNA levels and promotes extracellular Aβ accumulation. Site-directed mutagenesis of these two promoter sites reverses NICD-mediated IDE repression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 AD mice induces HES-1/Hey-1 overexpression and reduces IDE mRNA, linking Notch signaling to IDE-mediated Aβ metabolism in vivo. Luciferase promoter reporter assays; site-directed mutagenesis of IDE promoter; transient transfection of NICD, HES-1, Hey-1; qRT-PCR for IDE mRNA; in vivo JAG-1 intracranial injection in Tg2576 mice; Aβ ELISA Biochimica et biophysica acta High 22036964
2012 IDE is upregulated in a heat shock protein (HSP)-like manner in normal and malignant cells exposed to various stresses. IDE-silencing in neuroblastoma (SH-SY5Y) cells inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin in SH-SY5Y cells, and IDE inhibition is accompanied by a decrease in poly-ubiquitinated protein content, suggesting IDE participates in ubiquitin/proteasome protein quality control. Stress-induced IDE expression analysis; siRNA knockdown with cell proliferation and viability assays; co-immunoprecipitation of IDE with proteasome and ubiquitin; western blotting for poly-ubiquitinated proteins The Journal of biological chemistry Medium 23188819
2011 BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing the levels of secreted IDE, a major Aβ-degrading protease. This effect is observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and is retained by BRI2 lacking its C-terminal 23-amino acid peptide, indicating BRI2 acts as a regulatory protein modulating extracellular IDE levels to influence Aβ metabolism. BRI2/ADanPP overexpression in cells; Aβ ELISA of conditioned medium; western blot and ELISA for secreted IDE; BRI2 C-terminal truncation constructs; AD mouse model plaque load assessment The Journal of biological chemistry Medium 21873424
2013 Ide knockout (KO) mice exhibit decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable pool of insulin granules, and the Ide gene is haploinsufficient for this phenotype. Autophagic flux and microtubule content are reduced in β-cells of Ide KO mice. IDE and α-synuclein levels are inversely correlated in β-cells of Ide KO mice and T2D patients, and both gain and loss of function of α-synuclein in β-cells in vivo impair GSIS and autophagy, establishing IDE as a regulator of β-cell function through control of amyloidogenic α-synuclein levels. Ide KO and haploinsufficient mouse models; in vivo GSIS assays; autophagy flux assays; immunofluorescence for microtubules; quantitative IDE and α-synuclein protein measurements; α-synuclein gain/loss-of-function transgenic models in vivo Diabetes High 23349488
2019 SIRT4 interacts with PTEN and facilitates its degradation through IDE via the lysosomal pathway in response to nutritional starvation. SIRT4 bridges PTEN and IDE for degradation independently of PTEN acetylation or ubiquitination. Overexpression of SIRT4 causes down-regulation of PTEN, and this regulation is abrogated when IDE is inhibited, establishing IDE as a lysosomal protease mediating SIRT4-dependent PTEN degradation under stress conditions. Co-immunoprecipitation of SIRT4 with PTEN and IDE; SIRT4 overexpression with PTEN protein quantification; IDE inhibition rescue experiments; lysosome pathway inhibitors; nutritional starvation stress conditions FASEB journal Medium 30649986
2017 Sorting nexin 5 (SNX5) co-localizes with IDE at the plasma membrane and perinuclear area in human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 in hRPTCs decreases IDE expression and activity. Renal-selective silencing of Snx5 in mice decreases IDE protein and urinary insulin excretion, impairs insulin/glucose responses, and increases blood insulin and glucose, establishing SNX5 as a positive regulator of IDE expression and function in the kidney. Co-immunofluorescence localization; co-immunoprecipitation; siRNA knockdown in hRPTCs with IDE activity assays; renal-selective in vivo Snx5 silencing via osmotic mini-pump; glucose/insulin tolerance tests; spontaneously hypertensive rat (SHR) comparisons Diabetologia High 29080975
2009 ApoE4, compared to ApoE2 and ApoE3, significantly reduces IDE protein levels in hippocampal neurons. This reduction is blocked by NMDA receptor inhibitors and by RAP (receptor-associated protein, blocking LDL receptor family interactions), indicating ApoE4 acts through its receptor to stimulate the NMDA receptor pathway. Inhibition of NMDA receptor increases IDE levels, while NMDA receptor activation decreases IDE expression. The cAMP-dependent protein kinase (PKA) pathway acts downstream of the NMDA receptor to mediate NMDA-induced IDE repression. ApoE isoform treatment of primary hippocampal neurons; NMDA receptor inhibitors and activators; RAP blockade; PKA inhibitor/activator pharmacology; western blotting for IDE protein Neuroscience letters Medium 19616072
2010 A previously unreported IDE promoter SNP, rs6583817, is unequivocally associated with increased IDE transcript levels in human cerebella (p=1.5×10⁻⁸, fold-increase=2.12). In vitro dual luciferase reporter assays confirm rs6583817 increases reporter gene expression in Be(2)-C and HepG2 cell lines. A proxy for rs6583817 is associated with decreased plasma Aβ40 levels in a population cohort, and rs6583817 is associated with decreased risk of late-onset Alzheimer's disease, establishing a functional regulatory variant in the IDE promoter that links IDE expression level to Aβ metabolism. Dual luciferase reporter assay in two cell lines; eQTL analysis of IDE transcript levels in 194 LOAD cerebella; GWAS proxy analysis for plasma Aβ40; case-control association in 3,891 AD cases and 3,605 controls PloS one Medium 20098734
2023 In IDE knockout (IDE-KO) mice, specific microgliosis is induced in the hippocampus without effects on hippocampal volume or astrogliosis, revealing a non-enzymatic role for IDE in regulating microglial phenotype. Primary microglial cultures from IDE-KO mice show impaired modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management, indicating that IDE's microglial function cannot be explained solely by its proteolytic activity. IDE-KO mouse model; immunohistochemistry for microglia and astrocytes; hippocampal volume measurement; behavioral memory testing; primary microglial culture from wildtype and IDE-KO mice with functional phenotyping assays Journal of neuroinflammation Medium 37817156

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. The New England journal of medicine 591 36762851
2009 Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 564 19737565
2008 Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 188 18633108
2001 The ins(ide) and out(side) of dolichyl phosphate biosynthesis and recycling in the endoplasmic reticulum. Glycobiology 150 11425794
2016 Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. Journal of hepatology 146 27639844
2018 Hepatitis B Virus Serum DNA andRNA Levels in Nucleos(t)ide Analog-Treated or Untreated Patients During Chronic and Acute Infection. Hepatology (Baltimore, Md.) 138 29734472
2012 Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. Journal of hepatology 134 22659518
2015 Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues. The Journal of infectious diseases 127 26216905
2012 High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 119 23137006
2016 Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B. The Journal of infectious diseases 115 27609808
2023 Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood cancer journal 106 37558706
2007 Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. The Journal of biological chemistry 106 17613531
2019 Association Between Negative Results From Tests for HBV DNA and RNA and Durability of Response After Discontinuation of Nucles(t)ide Analogue Therapy. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 92 31362119
2017 Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial. The lancet. Gastroenterology & hepatology 92 28404133
2013 The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes 87 23349488
2023 A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B. Journal of hepatology 81 37062574
2008 Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease. Neurobiology of aging 76 19019493
2003 Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Human mutation 76 14517947
2015 Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology (Baltimore, Md.) 75 26361374
2017 Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment? Journal of clinical microbiology 74 28747369
2013 Ginsenoside Rg1 decreases Aβ(1-42) level by upregulating PPARγ and IDE expression in the hippocampus of a rat model of Alzheimer's disease. PloS one 71 23520555
2012 Insulin-degrading enzyme (IDE): a novel heat shock-like protein. The Journal of biological chemistry 71 23188819
2017 Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy. Journal of viral hepatitis 68 28185363
2018 Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss. The Journal of infectious diseases 60 29471497
2009 Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes. Journal of molecular medicine (Berlin, Germany) 59 19809796
2019 Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift. Hepatology international 55 31559604
2004 Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes 55 15277398
2018 Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer's disease: possible mechanisms of IDE in T2D and AD. Bioscience reports 54 29222348
2020 Effect of combination treatment based on interferon and nucleos(t)ide analogues on functional cure of chronic hepatitis B: a systematic review and meta-analysis. Hepatology international 52 33185803
2007 Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population. The Journal of clinical endocrinology and metabolism 52 17971426
2003 Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility. Diabetes 50 12716770
2021 Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma. Future oncology (London, England) 49 34854741
2022 Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. Journal of hepatology 48 35714812
2010 Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease. PloS one 45 20098734
2008 Increased expression of Abeta degrading enzyme IDE in the cortex of transgenic mice with Alzheimer's disease-like neuropathology. Neuroscience letters 45 18455870
2021 Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 41 33895361
2016 The ins(ide) and outs(ide) of asymmetric stem cell division. Current opinion in cell biology 41 27318429
2015 Construction of Au-IDE/CFP10-ESAT6 aptamer/DNA-AuNPs MSPQC for rapid detection of Mycobacterium tuberculosis. Biosensors & bioelectronics 40 26513286
2024 JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2. Journal of hepatology 39 38583491
2013 The efficacy and safety of nucleos(t)ide analogues in the treatment of HBV-related acute-on-chronic liver failure: a meta-analysis. Annals of hepatology 38 23619252
2011 BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). The Journal of biological chemistry 38 21873424
2008 Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Abeta and insulin degradation. Molecular neurodegeneration 38 19117523
2014 Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment. International journal of molecular sciences 37 25421241
2011 Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism. Biochimica et biophysica acta 37 22036964
2017 Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs. Frontiers of medicine 36 29170915
2023 Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients. BMC cancer 35 37061680
2024 EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma. Journal for immunotherapy of cancer 34 39379098
2019 SIRT4 regulates PTEN stability through IDE in response to cellular stresses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30649986
2019 Dietary curcumin enhances insulin clearance in diet-induced obese mice via regulation of hepatic PI3K-AKT axis and IDE, and preservation of islet integrity. Nutrition & metabolism 32 31372175
2021 Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatology communications 31 34558833
2020 Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B. Antiviral research 31 33279523
2022 Association of Serum Hepatitis B Virus RNA With Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Under Nucleos(t)ide Analogues Therapy. The Journal of infectious diseases 30 34931674
2025 ACURATE neo2 valve versus commercially available transcatheter heart valves in patients with severe aortic stenosis (ACURATE IDE): a multicentre, randomised, controlled, non-inferiority trial. Lancet (London, England) 29 40412426
2023 Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer's disease and brain aging. Journal of neuroinflammation 29 37817156
2019 Comparative efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B: A systematic review and meta-analysis. PloS one 29 31751366
2010 A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties. PloS one 29 20300529
2012 Discrepancy of potential antiviral resistance mutation profiles within the HBV reverse transcriptase between nucleos(t)ide analogue-untreated and -treated patients with chronic hepatitis B in a hospital in China. Journal of medical virology 28 22170539
2008 Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best practice & research. Clinical gastroenterology 28 19187868
2018 Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are Broad-Spectrum Antiviral Drugs that Activate Innate Immunity. Viruses 27 29677162
2017 cAMP/PKA signaling pathway contributes to neuronal apoptosis via regulating IDE expression in a mixed model of type 2 diabetes and Alzheimer's disease. Journal of cellular biochemistry 27 28771808
2009 ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neuroscience letters 26 19616072
2019 Selected nucleos(t)ide-based prescribed drugs and their multi-target activity. European journal of pharmacology 25 31634460
2020 Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation. Endocrine regulations 24 32857715
2014 IDE (rs6583817) polymorphism and pulse pressure are independently and interactively associated with level and change in executive function in older adults. Psychology and aging 24 24660790
2022 Ginsenoside F1 Protects the Brain against Amyloid Beta-Induced Toxicity by Regulating IDE and NEP. Life (Basel, Switzerland) 23 35054451
2022 Impact of preexisting nucleos(t)ide reverse transcriptase inhibitor resistance on the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide in treatment experience patients. AIDS (London, England) 23 35848506
2023 Antiviral activities of two nucleos(t)ide analogs against vaccinia, mpox, and cowpox viruses in primary human fibroblasts. Antiviral research 21 37270160
2013 Mutations in HBV DNA polymerase associated with nucleos(t)ide resistance are rare in treatment-naive patients. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 21 24342744
2012 Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues. World journal of gastroenterology 21 23326119
2024 Predictors of hepatic flares after nucleos(t)ide analogue cessation - Results of a global cohort study (RETRACT-B study). Journal of hepatology 20 39773379
2021 Resequencing and SNP discovery of Amur ide (Leuciscus waleckii) provides insights into local adaptations to extreme environments. Scientific reports 20 33658614
2022 Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepatic medicine : evidence and research 19 35936810
2017 Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 19 29080975
2023 Phase 2 results of idecabtagene vicleucel (ide-cel, bb2121) in Japanese patients with relapsed and refractory multiple myeloma. International journal of hematology 18 36690910
2020 Serum HBV RNA Dynamic and Drug Withdrawal Predictor Value in Patients With Chronic HBV Infection on Long-term Nucleos(t)ide Analogue (NA) Therapy. Journal of clinical gastroenterology 18 32604147
2017 Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis. Expert review of anti-infective therapy 18 28317397
2015 Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma. World journal of hepatology 18 26167247
2010 Association between variants in IDE-KIF11-HHEX and plasma amyloid β levels. Neurobiology of aging 18 20724036
2008 Loci of TCF7L2, HHEX and IDE on chromosome 10q and the susceptibility of their genetic polymorphisms to type 2 diabetes. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 18 19053027
1974 Properties of Protochlorophyllide and Chlorophyll(ide) Holochromes from Etiolated and Greening Leaves. Plant physiology 18 16658717
2016 Nucleos(t)ide analogues causes HBV S gene mutations and carcinogenesis. Hepatobiliary & pancreatic diseases international : HBPD INT 17 27919846
2023 Differential response of HBV envelope-specific CD4 + T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy. Hepatology (Baltimore, Md.) 16 36896974
2021 Matching adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121) versus selinexor + dexamethasone and belantamab mafodotin in relapsed and refractory multiple myeloma. Leukemia & lymphoma 16 33896344
2020 Detectable HBV DNA during nucleos(t)ide analogues stratifies predictive hepatocellular carcinoma risk score. Scientific reports 16 32747646
2020 Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B. Cells 15 32093411
2023 Analysis of patient-reported experiences up to 2 years after receiving idecabtagene vicleucel (ide-cel, bb2121) for relapsed or refractory multiple myeloma: Longitudinal findings from the phase 2 KarMMa trial. Leukemia research 14 37087950
2021 Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients. Medicine 14 34260535
2021 Effects of Bicarbonate Stress on Serum Ions and Gill Transporters in Alkali and Freshwater Forms of Amur Ide (Leuciscus waleckii). Frontiers in physiology 14 34594232
2022 Finite nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B: From an "option" to an "active recommendation". The Kaohsiung journal of medical sciences 13 35262284
2016 Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues. Liver international : official journal of the International Association for the Study of the Liver 13 26931636
2015 A Better Antiviral Efficacy Found in Nucleos(t)ide Analog (NA) Combinations with Interferon Therapy than NA Monotherapy for HBeAg Positive Chronic Hepatitis B: A Meta-Analysis. International journal of environmental research and public health 13 26308024
2024 Rh proteins and H+ transporters involved in ammonia excretion in Amur Ide (Leuciscus waleckii) under high alkali exposure. Ecotoxicology and environmental safety 12 38432157
2022 Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues. Journal of viral hepatitis 12 35274400
2022 Arthrospira Enhances Seroclearance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogue through Modulation of TNF-α/IFN-γ Profile. Nutrients 12 35889747
2016 Prevalence of mutations in HBV DNA polymerase gene associated with nucleos(t)ide resistance in treatment-naive patients with Chronic Hepatitis B in Central China. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases 12 26876337
2012 Tolerability and efficacy of anti-HBV nucleos(t)ide analogues in HBV-DNA-positive cirrhotic patients with HBV/HCV dual infection. Journal of viral hepatitis 12 23121368
2014 Telbivudine versus entecavir for nucleos(t)ide-naive HBeAg-positive chronic hepatitis B: a meta-analysis. The American journal of the medical sciences 11 23563307
2011 Treatment of HBeAg-positive chronic hepatitis B with nucleos(t)ide analogues. Liver international : official journal of the International Association for the Study of the Liver 11 21205143
2010 Therapy with nucleos(t)ide analogues: current role in dialysis patients. The International journal of artificial organs 11 20669138
2024 Limited Sustained Remission After Nucleos(t)ide Analog Withdrawal: Results From a Large, Global, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study). The American journal of gastroenterology 10 38483300

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