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Cited by 72Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAdvanced Glycation End Products research

RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia

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Sbai, Oualid, Djelloul, Mehdi, Auletta, Antonia, Ieraci, Alessandro, Vascotto, Carlo, Perrone, L.·2022·Cell Death & Disease
DOI 10.1038/s41419-022-04758-0PMC PMC8980056
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Abstract

Alzheimer's disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE-TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.

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  • Aβ shuttling into mitochondria exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation.

    “Aβ shuttling into mitochondria exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation.334”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [334]

  • Binding of Aβ to RAGE mediates Aβ transport from the cellular surface to mitochondria in microglia.

    “The binding of Aβ to RAGE mediates Aβ transport from the cellular surface to mitochondria in microglia.”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [334]

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References 69 · Cited by 72

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  1. [1]Prince M Ali GC Guerchet M Prina AM Albanese E Wu YT Recent global trends in the prevalence and incidence of dementia, and survival with dementia Alzheimers Res Ther 2016 8 23 27473681 PMC4967299
  2. [3]Perez Ortiz JM Swerdlow RH Mitochondrial dysfunction in Alzheimer’s disease: role in pathogenesis and novel therapeutic opportunities Br J Pharm 2019 176 3489 507. PMC6715612 30675901
  3. [6]Vom Berg J Prokop S Miller KR Obst J Kälin RE Lopategui-Cabezas I Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline Nat Med 2012 18 1812 9 23178247
  4. [7]Heneka MT Carson MJ El Khoury J Landreth GE Brosseron F Feinstein DL Neuroinflammation in Alzheimer’s disease Lancet Neurol 2015 14 388 405 25792098 PMC5909703
  5. [9]Groslambert M Py BF Spotlight on the NLRP3 inflammasome pathway J Inflamm Res 2018 11 359 74. 30288079 PMC6161739
  6. [10]Kelley N Jeltema D Duan Y He Y The NLRP3 inflammasome: an overview of mechanisms of activation and regulation Int J Mol Sci 2019 20 3328 31284572 PMC6651423
  7. [11]Weber ANR Bittner ZA Shankar S Liu X Chang TH Jin T Recent insights into the regulatory networks of NLRP3 inflammasome activation J Cell Sci 2020 133 jcs248344 33273068
  8. [13]Kim SY Suh HW Chung JW Yoon SR Choi I Diverse functions of VDUP1 in cell proliferation, differentiation, and diseases Cell Mol Immunol 2007 4 345 51 17976314
  9. [14]Perrone L Valente M The emerging role of metabolism in brain-heart axis: new challenge for the therapy and prevention of Alzheimer disease. may thioredoxin interacting protein (TXNIP) play a role? Biomolecules 2021 11 1652 34827650 PMC8616009
  10. [15]Fertan E Rodrigues GJ Wheeler RV Goguen D Wong AA James H Cognitive decline, cerebral-spleen tryptophan metabolism, oxidative stress, cytokine production, and regulation of the txnip gene in a triple transgenic mouse model of alzheimer disease Am J Pathol 2019 189 1435 50. 30980800
  11. [16]Li L Ismael S Nasoohi S Sakata K Liao FF McDonald MP Thioredoxin-interacting protein (TXNIP) associated NLRP3 inflammasome activation in human Alzheimer’s disease brain J Alzheimers Dis 2019 68 255 65. 30741672 PMC10947081
  12. [17]Melone MAB Dato C Paladino S Coppola C Trebini C Giordana M Verapamil inhibits Ser202/Thr205 phosphorylation of tau by blocking TXNIP/ROS/p38 MAPK pathway Pharm Res 2018 35 44 29404777
  13. [18]Nasoohi S Parveen K Ishrat T Metabolic syndrome, brain insulin resistance, and alzheimer’s disease: thioredoxin interacting protein (TXNIP) and inflammasome as core amplifiers J Alzheimers Dis 2018 66 857 85. 30372683
  14. [19]Perrone L Sbai O Nawroth PP Bierhaus A The complexity of sporadic Alzheimer’s disease pathogenesis: the role of RAGE as therapeutic target to promote neuroprotection by inhibiting neurovascular dysfunction Int J Alzheimers Dis 2012 2012 734956 66 22482078 PMC3310161
  15. [20]Huang YY Fang N Luo H Gao F Zou Y Zhou LL RP1, a RAGE antagonist peptide, can improve memory impairment and reduce Abeta plaque load in the APP/PS1 mouse model of Alzheimer’s disease Neuropharmacology 2020 180 108304 32931813
  16. [21]Criscuolo C Fontebasso V Middei S Stazi M Ammassari-Teule M Yan SS Entorhinal cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model Sci Rep 2017 7 42370 28205565 PMC5304222
  17. [22]Chen J Sun Z Jin M Tu Y Wang S Yang X Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-κB pathway J Neuroimmunol 2017 305 108 14. 28284330
  18. [23]Perrone L Devi TS Hosoya KC Terasaki T Singh LP Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions J Cell Physiol 2009 221 262 72 19562690
  19. [24]Sbai O Devi TS Melone MAB Feron F Khrestchatisky M Singh LP RAGE–TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion J Cell Sci 2010 123 4332 9 21098642
  20. [25]Yeh WJ Yang HY Pai MH Wu CH Chen JR Long-term administration of advanced glycation end-product stimulates the activation of NLRP3 inflammasome and sparking the development of renal injury J Nutr Biochem 2017 39 68 76 27816762
  21. [26]Chen J Cha-Molstad H Szabo A Shalev A Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein Am J Physiol Endocrinol Metab 2009 296 E1133 E9. 19258488 PMC2681312
  22. [27]Xu L Lin X Guan M Zeng Y Liu Y Verapamil attenuated prediabetic neuropathy in high-fat diet-fed mice through inhibiting TXNIP-mediated apoptosis and inflammation Oxid Med Cell Longev 2019 2019 1896041 30733849 PMC6348807
  23. [28]Tsubaki H Tooyama I Walker DG Thioredoxin-interacting protein (TXNIP) with focus on brain and neurodegenerative diseases Int J Mol Sci 2020 21 9357 33302545 PMC7764580
  24. [29]Kandimalla R Reddy PH Multiple faces of dynamin-related protein 1 and its role in Alzheimer’s disease pathogenesis Biochim Biophys Acta 2016 1862 814 28. 26708942 PMC5343673
  25. [30]Kageyama Y Zhang Z Sesaki H Mitochondrial division: molecular machinery and physiological functions Curr Opin Cell Biol 2011 23 427 34 21565481 PMC3379813
  26. [31]Moretti J Blander JM Increasing complexity of NLRP3 inflammasome regulation J Leukoc Biol 2020 109 561 57 32531835 PMC8985609
  27. [32]Nasoohi S Ismael S Ishrat T Thioredoxin-interacting protein (TXNIP) in cerebrovascular and neurodegenerative diseases: regulation and implication Mol Neurobiol 2018 55 7900 20. 29488135 PMC6388721
  28. [33]Hokama M Oka S Leon J Ninomiya T Honda H Sasaki K Altered expression of diabetes-related genes in Alzheimer’s disease brains: the Hisayama study Cereb Cortex 2014 24 2476 88 23595620 PMC4128707
  29. [34]Wang Y Wang Y Bharti V Zhou H Hoi V Tan H Upregulation of thioredoxin-interacting protein in brain of amyloid-β protein precursor/presenilin 1 transgenic mice and amyloid-β treated neuronal cells J Alzheimers Dis 2019 72 139 50. 31561358
  30. [35]Xu G Chen J Jing G Shalev A Preventing β-cell loss and diabetes with calcium channel blockers Diabetes 2012 61 848 56 22442301 PMC3314354
  31. [36]Popović N Morales-Delgado N Vidal Mena D Alonso A Pascual Martínez M Caballero Bleda M Verapamil and Alzheimer’s disease: past, present, and future Front Pharm 2020 11 562 PMC7214748 32431612
  32. [37]Popović M Caballero-Bleda M Popović N Bokonjić D Dobrić S Neuroprotective effect of chronic verapamil treatment on cognitive and noncognitive deficits in an experimental Alzheimer’s disease in rats Int J Neurosci 1997 92 79 93 9522258
  33. [38]Abuznait AH Cain C Ingram D Burk D Kaddoumi A Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer’s disease J Pharm Pharm 2011 63 1111 8 PMC3163078 21718295
  34. [39]Chavakis T Bierhaus A Nawroth PP RAGE (receptor for advanced glycation end products): a central player in the inflammatory response Microbes Infect 2004 6 1219 25 15488742
  35. [40]Riuzzi F Sorci G Sagheddu R Chiappalupi S Salvadori L Donato R RAGE in the pathophysiology of skeletal muscle J Cachexia Sarcopenia Muscle 2018 9 1213 34 30334619 PMC6351676
  36. [41]Vincent A Perrone L Sullivan K Backus C Sastry A Lastoskie C Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress Endocrinology 2007 148 548 58 17095586
  37. [44]Neher JJ Cunningham C Priming microglia for innate immune memory in the brain Trends Immunol 2019 40 358 74. 30833177
  38. [45]Saxena G Chen J Shalev A Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein J Biol Chem 2010 285 3997 4005 19959470 PMC2823541
  39. [46]Waldhart AN Dykstra H Peck AS Boguslawski EA Madaj ZB Wen J Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin Cell Rep 2017 19 2005 13. 28591573 PMC5603216
  40. [47]Wu N Zheng B Shaywitz A Dagon Y Tower C Bellinger G AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1 Mol Cell 2013 49 1167 75 23453806 PMC3615143
  41. [48]Mazarguil H Leveque C Bartnik D Fantini J Gouget T Funke SA A synthetic amino acid substitution of Tyr10 in Aβ peptide sequence yields a dominant negative variant in amyloidogenesis Aging Cell 2012 11 530 41 22385841
  42. [50]Lesné S Kotilinek L Ashe KH Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function Neuroscience 2008 151 745 9 18155846 PMC2677385
  43. [52]Vantaggiato C Castelli M Giovarelli M Orso G Bassi MT Clementi E The fine tuning of Drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation Front Cell Neurosci 2019 13 120 31019453 PMC6458285
  44. [53]Manczak M Reddy PH Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: implications for mitochondrial dysfunction and neuronal damage Hum Mol Genet 2012 21 2538 47 22367970 PMC3349426
  45. [54]Manczak M Calkins MJ Reddy PH Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage Hum Mol Genet 2011 20 2495 509 21459773 PMC3109997
  46. [56]Xie N Wang C Lian Y Wu C Zhang H Zhang Q Inhibition of mitochondrial fission attenuates Aβ-induced microglia apoptosis Neuroscience 2014 256 36 42 24144623
  47. [57]Agrawal I Jha S Mitochondrial dysfunction and Alzheimer’s disease: role of microglia Front Aging Neurosci 2020 12 252 32973488 PMC7468434
  48. [58]Hamilton C Anand PK Right place, right time: localisation and assembly of the NLRP3 inflammasome F1000Res 2019 8 676 PMC6530608 31131091
  49. [59]Zhou R Yazdi AS Menu P Tschopp J A role for mitochondria in NLRP3 inflammasome activation Nature 2011 469 221 5 21124315
  50. [60]Wang HM Zhang T Huang JK Xiang JY Chen JJ Fu JL Edaravone attenuates the proinflammatory response in Amyloid-β-treated microglia by inhibiting NLRP3 inflammasome-mediated IL-1β secretion Cell Physiol Biochem 2017 43 1113 25. 28977782
  51. [61]Guo M Wang X Zhao Y Yang Q Ding H Dong Q Ketogenic diet improves brain ischemic tolerance and inhibits NLRP3 inflammasome activation by preventing drp1-mediated mitochondrial fission and endoplasmic reticulum stress Front Mol Neurosci 2018 11 86 29662437 PMC5890101
  52. [62]Youm YH Grant RW McCabe LR Albarado DC Nguyen KY Ravussin A Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging Cell Metab 2013 18 519 32 24093676 PMC4017327
  53. [64]Alexiou P Chatzopoulou M Pegklidou K Demopoulos VJ RAGE: a multi-ligand receptor unveiling novel insights in health and disease Curr Med Chem 2010 17 2232 52 20459381
  54. [65]Bharti V Tan H Zhou H Wang JF Txnip mediates glucocorticoid-activated NLRP3 inflammatory signaling in mouse microglia Neurochem Int 2019 131 104564 31586460
  55. [66]Xu Q Xing H Wu J Chen W Zhang N miRNA-141 induced pyroptosis in intervertebral disk degeneration by targeting ROS Generation and activating TXNIP/NLRP3 signaling in nucleus pulpous cells Front Cell Dev Biol 2020 8 871 32984347 PMC7487322
  56. [67]Chang YH Lin HY Shen FC Su YJ Chuang JH Lin TK The causal role of mitochondrial dynamics in regulating innate immunity in diabetes Front Endocrinol (Lausanne) 2020 11 455 32849261 PMC7403198

Authors
Sbai, O., Djelloul, M., Auletta, A., Ieraci, A., Vascotto, C., & Perrone, L.
Affiliations
  • Aix-Marseille Université (FR)
  • University of Campania "Luigi Vanvitelli" (IT)
  • University of Milan (IT)
  • University of Udine (IT)
  • German Cancer Research Center (DE)
Corresponding author
  • Vascotto, Carlo
  • Perrone, L.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2022-04-04
Volume
13
Issue
4
Pages
302-302
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-022-04758-0
PMC
PMC8980056
OpenAlex
W4223473335
Cited by
72
References
69
Citations by year
2026: 16 · 2025: 11 · 2024: 23 · 2023: 14 · 2022: 8
FWCI
8.82
Type
journal article
Language
en
Update notices
correction (2022-04-19)
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Institutional Research Information System (University of Udine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IRIS eCampus Telematic University (Università degli Studi eCampus) (submittedVersion)
Funders
  • Deutsches Krebsforschungszentrum
  • European Commission (2014‐2020, HORIZON2020, 956070)
  • Agence Nationale de la Recherche (ANR-10-MALZ-0005)
  • Centre National de la Recherche Scientifique
  • Ministero dello Sviluppo Economico (HORIZON2020, F/050347/01-03/X32)
  • Université de Poitiers
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Keywords
Alzheimer's disease, RAGE, TXNIP, amyloid-beta, microglia, neuroinflammation, mitochondrial dysfunction, Drp1, NLRP3 inflammasome, IL-1β, pyroptosis, gasdermin D, oxidative stress, 5xFAD mice, glial fibrillary acidic protein
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Alzheimer Disease, Animals, Carrier Proteins, Inflammation, Mitochondria, Thioredoxins, Amyloid beta-Peptides, Microglia, Mice, Inflammasomes

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