Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Insulins | Research

Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging

Authors: Miriam Corraliza-Gomez, Teresa Bermejo, Jingtao Lilue, Noelia Rodriguez-Iglesias, Jorge Valero, Irene Cozar-Castellano, Eduardo Arranz, Diego Sanchez, Maria Dolores Ganfornina

Published in: Journal of Neuroinflammation | Issue 1/2023

Login to get access

Abstract

The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.
Appendix
Available only for authorised users
Literature
1.
2.
Gong C-X, Liu F, Iqbal K. Multifactorial hypothesis and multi-targets for Alzheimer’s disease. J Alzheimers Dis. 2018;64:S107–17.PubMedCrossRef
3.
4.
Tohidpour A, Morgun AV, Boitsova EB, Malinovskaya NA, Martynova GP, Khilazheva ED, et al. Neuroinflammation and infection: molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol. 2017;7:276.PubMedPubMedCentralCrossRef
5.
6.
7.
Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.PubMedCrossRef
8.
9.
Paolicelli RC, Sierra A, Stevens B, Tremblay M-E, Aguzzi A, Ajami B, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110:3458–83.PubMedPubMedCentralCrossRef
10.
World Health Organization. Classification of diabetes mellitus. Geneva: World Health Organization; 2019.
11.
Bach J-F. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994;15:27.CrossRef
12.
Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–83.PubMedCrossRef
13.
De la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. JAD. 2005;7:45–61.PubMedCrossRef
14.
Ramos-Rodriguez JJ, Spires-Jones T, Pooler AM, Lechuga-Sancho AM, Bacskai BJ, Garcia-Alloza M. Progressive neuronal pathology and synaptic loss induced by prediabetes and type 2 diabetes in a mouse model of Alzheimer’s disease. Mol Neurobiol. 2017;54:3428–38.PubMedCrossRef
15.
Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler MMB. Association of diabetes mellitus and dementia: the Rotterdam study. Diabetologia. 1996;39:1392–7.PubMedCrossRef
16.
Kuusisto J, Koivisto K, Mykkanen L, Helkala E-L, Vanhanen M, Hanninen T, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein e4 phenotype: cross sectional population based study. BMJ. 1997;315:1045–9.PubMedPubMedCentralCrossRef
17.
Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 1999;16:93–112.PubMedCrossRef
18.
Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145:301–8.PubMedCrossRef
19.
Ott A, Stolk RP, van Harskamp F, Pols HAP, Hofman A, Breteler MMB. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53:1937–1937.PubMedCrossRef
20.
Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661.PubMedCrossRef
21.
Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology. 2004;63:1181–6.PubMedCrossRef
22.
Corraliza-Gómez M, Lillo C, Cózar-Castellano I, Arranz E, Sanchez D, Ganfornina MD. Evolutionary origin of insulin-degrading enzyme and its subcellular localization and secretion mechanism: a study in microglial cells. Cells. 2022;11:227.PubMedPubMedCentralCrossRef
23.
Broh-Kahn R, Mirsky I. The inactivation of insulin by tissue extracts; the effect of fasting on the insulinase content of rat liver. Arch Biochem. 1949;20:10–4.PubMed
24.
González-Casimiro CM, Merino B, Casanueva-Álvarez E, Postigo-Casado T, Cámara-Torres P, Fernández-Díaz CM, et al. Modulation of insulin sensitivity by insulin-degrading enzyme. Biomedicines. 2021;9:86.PubMedPubMedCentralCrossRef
25.
Kurochkin IV, Goto S. Alzheimer’s β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345:33–7.PubMedCrossRef
26.
Kuo WL, Montag AG, Rosner MR. Insulin-degrading enzyme is differentially expressed and developmentally regulated in various rat tissues. Endocrinology. 1993;132:604–11.PubMedCrossRef
27.
Bertram L. Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science. 2000;290:2302–3.PubMedCrossRef
28.
Myers A. Susceptibility locus for Alzheimer’s disease on chromosome 10. Science. 2000;290:2304–5.PubMedCrossRef
29.
Bian L, Yang JD, Guo TW, Sun Y, Duan SW, Chen WY, et al. Insulin-degrading enzyme and Alzheimer disease: a genetic association study in the Han Chinese. Neurology. 2004;63:241–5.PubMedCrossRef
30.
Björk BF, Katzov H, Kehoe P, Fratiglioni L, Winblad B, Prince JA, et al. Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE. Neurobiol Aging. 2007;28:1374–80.PubMedCrossRef
31.
Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, et al. Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer’s disease. Hum Mol Genet. 2007;16:2703–12.PubMedCrossRef
32.
Liu F, Arias-Vásquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, et al. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet. 2007;81:17–31.PubMedPubMedCentralCrossRef
33.
Vepsalainen S, Parkinson M, Helisalmi S, Mannermaa A, Soininen H, Tanzi RE, et al. Insulin-degrading enzyme is genetically associated with Alzheimer’s disease in the Finnish population. J Med Genet. 2007;44:606–8.PubMedPubMedCentralCrossRef
34.
Zuo X, Jia J. Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer’s disease. Brain Res. 2009;1249:1–8.PubMedCrossRef
35.
Carrasquillo MM, Belbin O, Zou F, Allen M, Ertekin-Taner N, Ansari M, et al. Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Aß, and Alzheimer’s disease. PLoS ONE. 2010;5: e8764.PubMedPubMedCentralCrossRef
36.
Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, et al. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet. 1999;64:1127–40.PubMedPubMedCentralCrossRef
37.
Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, et al. A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (The Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet. 2001;69:553–69.PubMedPubMedCentralCrossRef
38.
Karamohamed S, Demissie S, Volcjak J, Liu C, Heard-Costa N, Liu J, et al. Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham heart study. Diabetes. 2003;52:1562–7.PubMedCrossRef
39.
Furukawa Y, Shimada T, Furuta H, Matsuno S, Kusuyama A, Doi A, et al. Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population. J Clin Endocrinol Metab. 2008;93:310–4.PubMedCrossRef
40.
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid -protein, and the -amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. 2003;100:4162–7.PubMedPubMedCentralCrossRef
41.
Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS ONE. 2011;6: e20818.PubMedPubMedCentralCrossRef
42.
Qiu W, Folstein M. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging. 2006;27:190–8.PubMedCrossRef
43.
Pivovarova O, Höhn A, Grune T, Pfeiffer AFH, Rudovich N. Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease? Ann Med. 2016;48:614–24.PubMedCrossRef
44.
45.
46.
47.
Sanchez D, Bajo-Grañeras R, Del Caño-Espinel M, Garcia-Centeno R, Garcia-Mateo N, Pascua-Maestro R, et al. Aging without apolipoprotein D: molecular and cellular modifications in the hippocampus and cortex. Exp Gerontol. 2015;67:19–47.PubMedCrossRef
48.
49.
Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988;31:47–59.PubMedCrossRef
50.
51.
Wolterink-Donselaar IG, Meerding JM, Fernandes C. A method for gender determination in newborn dark pigmented mice. Lab Anim. 2009;38:35–8.CrossRef
52.
Saura J, Tusell JM, Serratosa J. High-yield isolation of murine microglia by mild trypsinization. Glia. 2003;44:183–9.PubMedCrossRef
53.
54.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.PubMedCrossRef
55.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.PubMedCrossRef
56.
García-Alcalde F, Okonechnikov K, Carbonell J, Cruz LM, Götz S, Tarazona S, et al. Qualimap: evaluating next-generation sequencing alignment data. Bioinformatics. 2012;28:2678–9.PubMedCrossRef
57.
58.
59.
Kolberg L, Raudvere U, Kuzmin I, Vilo J, Peterson H. Dgprofiler2—an R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler. F1000Research. 2020;9:709.CrossRef
60.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.PubMedCrossRef
61.
García-Mateo N, Pascua-Maestro R, Pérez-Castellanos A, Lillo C, Sanchez D, Ganfornina MD. Myelin extracellular leaflet compaction requires apolipoprotein D membrane management to optimize lysosomal-dependent recycling and glycocalyx removal. Glia. 2018;66:670–87.PubMedCrossRef
62.
Bjerknes R, Bassoe C-F. Phagocyte C3-mediated attachment and internalization: flow cytometric studies using a fluorescence quenching technique. Blut. 1984;49:315–23.PubMedCrossRef
63.
64.
65.
Dorfman VB, Pasquini L, Riudavets M, López-Costa JJ, Villegas A, Troncoso JC, et al. Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer’s disease. Neurobiol Aging. 2010;31:1743–57.PubMedCrossRef
66.
Diaz-Aparicio I, Paris I, Sierra-Torre V, Plaza-Zabala A, Rodríguez-Iglesias N, Márquez-Ropero M, et al. Microglia actively remodel adult hippocampal neurogenesis through the phagocytosis secretome. J Neurosci. 2020;40:1453–82.PubMedPubMedCentralCrossRef
67.
68.
69.
Askew K, Gomez-Nicola D. A story of birth and death: Insights into the formation and dynamics of the microglial population. Brain Behav Immun. 2018;69:9–17.PubMedCrossRef
70.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.PubMedCrossRef
71.
Sousa L, Guarda M, Meneses MJ, Macedo MP, Vicente MH. Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases. J Pathol. 2021;255:346–61.PubMedCrossRef
72.
Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, et al. Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci. 2003;100:6221–6.PubMedPubMedCentralCrossRef
73.
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463–77.PubMedCrossRef
74.
Yanguas-Casás N, Crespo-Castrillo A, de Ceballos ML, Chowen JA, Azcoitia I, Arevalo MA, et al. Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid. Glia. 2018;66:522–37.PubMedCrossRef
75.
Qiu WQ, Ye Z, Kholodenko D, Seubert P, Selkoe DJ. Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem. 1997;272:6641–6.PubMedCrossRef
76.
Mandrekar S, Jiang Q, Lee CYD, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble Aβ through fluid phase macropinocytosis. J Neurosci. 2009;29:4252–62.PubMedPubMedCentralCrossRef
77.
Fu H, Liu B, Li L, Lemere CA. Microglia do not take up soluble amyloid-beta peptides, but partially degrade them by secreting insulin-degrading enzyme. Neuroscience. 2020;443:30–43.PubMedCrossRef
78.
79.
Olmos-Alonso A, Schetters STT, Sri S, Askew K, Mancuso R, Vargas-Caballero M, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016;139:891–907.PubMedPubMedCentralCrossRef
80.
Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 2017;18:391–405.PubMedPubMedCentralCrossRef
81.
Lee SC, Liu W, Roth P, Dickson DW, Berman JW, Brosnan CF. Macrophage colony-stimulating factor in human fetal astrocytes and microglia. Differential regulation by cytokines and lipopolysaccharide, and modulation of class II MHC on microglia. J Immunol (Baltimore, Md 1950). 1993;150:594–604.CrossRef
82.
Pivovarova O, von Loeffelholz C, Ilkavets I, Sticht C, Zhuk S, Murahovschi V, et al. Modulation of insulin degrading enzyme activity and liver cell proliferation. Cell Cycle. 2015;14:2293–300.PubMedPubMedCentralCrossRef
83.
Tundo GR, Sbardella D, Ciaccio C, Bianculli A, Orlandi A, Desimio MG, et al. Insulin-degrading enzyme (IDE). A novel heat shock-like protein. J Biol Chem. 2013;288:2281–9.PubMedCrossRef
84.
Wang M, Feng L-R, Li Z-L, Ma K-G, Chang K-W, Chen X-L, et al. Thymosin β4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice. J Neuroinflammation. 2021;18:146.PubMedPubMedCentralCrossRef
85.
Kulas JA, Franklin WF, Smith NA, Manocha GD, Puig KL, Nagamoto-Combs K, et al. Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues. Am J Physiol Endocrinol Metab. 2019;316:E106–20.PubMedCrossRef
86.
Tundo G, Ciaccio C, Sbardella D, Boraso M, Viviani B, Coletta M, et al. Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD. PLoS ONE. 2012;7: e34376.PubMedPubMedCentralCrossRef
87.
Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H. IL-4-induced selective clearance of oligomeric β-amyloid peptide 1–42 by rat primary type 2 microglia. J Immunol. 2008;181:6503–13.PubMedCrossRef
88.
Metadata
Title
Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
Authors
Miriam Corraliza-Gomez
Teresa Bermejo
Jingtao Lilue
Noelia Rodriguez-Iglesias
Jorge Valero
Irene Cozar-Castellano
Eduardo Arranz
Diego Sanchez
Maria Dolores Ganfornina
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02914-7

Other articles of this Issue 1/2023

Journal of Neuroinflammation 1/2023 Go to the issue

Research

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy

Research

Distinguishing the effects of systemic CSF1R inhibition by PLX3397 on microglia and peripheral immune cells

Research

Early miR-320b and miR-25-3p miRNA levels correlate with multiple sclerosis severity at 10 years: a cohort study

Research

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke

Research

Prominent epigenetic and transcriptomic changes in CD4+ and CD8+ T cells during and after pregnancy in women with multiple sclerosis and controls

Research

Extracellular vesicles from hiPSC-NSCs can prevent peripheral inflammation-induced cognitive dysfunction with inflammasome inhibition and improved neurogenesis in the hippocampus