CoChat
Sign Up
Cited by 52Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer’s progression

Open access
Codocedo, Juan F., Mera-Reina, Claudia, Bor-Chian Lin, Peter, Fallen, Paul B., Puntambekar, Shweta S., Casali, Brad T., Jury-Garfe, Nur, Martinez, Pablo +2 more·2024·Cell Reports
DOI 10.1016/j.celrep.2024.114488PMC PMC11398604
Open this paper in CoChat — free account

Abstract

Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2024.114488

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences.

    “Surprisingly, recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences, emphasizing the importance of exploring total PLCG2 loss.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [30]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 61 · Cited by 52

Research works printed but not linked: 44

  1. [1]Sasaki A, Yamaguchi H, Ogawa A, Sugihara S, and Nakazato Y. (1997). Microglial activation in early stages of amyloid beta protein deposition. Acta Neuropathol. 94, 316– 322. 10.1007/s004010050713. 9341931 · DOI · Paper page
  2. [2]Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, and Grutzendler J. (2016). TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 90, 724– 739. 10.1016/j.neuron.2016.05.003. 27196974 PMC4898967 · DOI · Paper page
  3. [3]d’Errico P, Ziegler-Waldkirch S, Aires V, Hoffmann P, Mezö C, Erny D, Monasor LS, Liebscher S, Ravi VM, Joseph K, (2022). Microglia contribute to the propagation of Aβ into unaffected brain tissue. Nat. Neurosci 25, 20– 25. 10.1038/s41593-021-00951-0. 34811521 PMC8737330 · DOI · Paper page
  4. [5]Jain N, Lewis CA, Ulrich JD, and Holtzman DM (2023). Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading. J. Exp. Med 220, e20220654. 10.1084/jem.20220654. PMC9559604 36219197 · DOI · Paper page
  5. [6]Ghosh S, Castillo E, Frias ES, and Swanson RA (2018). Bioenergetic regulation of microglia. Glia 66, 1200– 1212. 10.1002/glia.23271. 29219210 PMC5903989 · DOI
  6. [7]Loftus RM, and Finlay DK (2016). Immunometabolism: Cellular Metabolism Turns Immune Regulator. J. Biol. Chem 291, 1– 10. 10.1074/jbc.R115.693903. 26534957 PMC4697146 · DOI
  7. [8]Paolicelli RC, and Angiari S. (2019). Microglia immunometabolism: From metabolic disorders to single cell metabolism. Semin. Cell Dev. Biol 94, 129– 137. 10.1016/j.semcdb.2019.03.012. 30954657 · DOI
  8. [9]Gimeno-Bayón J, López-López A, Rodríguez MJ, and Mahy N. (2014). Glucose pathways adaptation supports acquisition of activated microglia phenotype. J. Neurosci. Res 92, 723– 731. 10.1002/jnr.23356. 24510633 · DOI
  9. [10]Pan R-Y, Ma J, Kong X-X, Wang X-F, Li S-S, Qi X-L, Yan Y-H, Cheng J, Liu Q, Jin W, (2019). Sodium rutin ameliorates Alzheimer’s disease–like pathology by enhancing microglial amyloid-β clearance. Sci. Adv 5, eaau6328. 10.1126/sciadv.aau6328. PMC6393001 30820451 · DOI
  10. [11]Fairley LH, Wong JH, and Barron AM (2021). Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease. Front. Immunol 12, 624538. 10.3389/fimmu.2021.624538. PMC7947196 33717134 · DOI · Paper page
  11. [12]Shen Y, Kapfhamer D, Minnella AM, Kim J-E, Won SJ, Chen Y, Huang Y, Low LH, Massa SM, and Swanson RA (2017). Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat. Commun 8, 624. 10.1038/s41467-017-00707-0. 28935892 PMC5608947 · DOI
  12. [13]Seki SM, and Gaultier A. (2017). Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity. Front. Immunol 8, 1549. 10.3389/fimmu.2017.01549. 29213268 PMC5702622 · DOI
  13. [14]De Jesus A, Keyhani-Nejad F, Pusec CM, Goodman L, Geier JA, Stoolman JS, Stanczyk PJ, Nguyen T, Xu K, Suresh KV, (2022). Hexokinase 1 cellular localization regulates the metabolic fate of glucose. Mol. Cell 82, 1261– 1277.e9. 10.1016/j.molcel.2022.02.028. 35305311 PMC8995391 · DOI
  14. [15]Codocedo JF, and Landreth GE (2022). The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose. Immunometabolism 4, e00011. 10.1097/IN9.0000000000000011. PMC9616595 36337735 · DOI
  15. [16]Granchi C, and Minutolo F. (2012). Anticancer Agents That Counteract Tumor Glycolysis. ChemMedChem 7, 1318– 1350. 10.1002/cmdc.201200176. 22684868 PMC3516916 · DOI
  16. [17]Baik SH, Ramanujan VK, Becker C, Fett S, Underhill DM, and Wolf AJ (2023). Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation. Sci. Immunol 8, eade7652. 10.1126/sciimmunol.ade7652. PMC10360408 37327321 · DOI
  17. [18]Leng L, Yuan Z, Pan R, Su X, Wang H, Xue J, Zhuang K, Gao J, Chen Z, Lin H, (2022). Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat. Metab 4, 1287– 1305. 10.1038/s42255-022-00643-4. 36203054 · DOI
  18. [19]Hu Y, Cao K, Wang F, Wu W, Mai W, Qiu L, Luo Y, Ge W-P, Sun B, Shi L, (2022). Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity. Nat. Metab 4, 1756– 1774. 10.1038/s42255-022-00707-5. 36536134 · DOI
  19. [20]Cheng J, Zhang R, Xu Z, Ke Y, Sun R, Yang H, Zhang X, Zhen X, and Zheng L-T (2021). Early glycolytic reprogramming controls microglial inflammatory activation. J. Neuroinflammation 18, 129. 10.1186/s12974-021-02187-y. 34107997 PMC8191212 · DOI · Paper page
  20. [21]Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu NI, Coggeshall KM, Arditi M, and Underhill DM (2016). Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell 166, 624– 636. 10.1016/j.cell.2016.05.076. 27374331 PMC5534359 · DOI
  21. [22]Sil A, Erfani A, Lamb N, Copland R, Riedel G, and Platt B. (2022). Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model.J. Alzheimers Dis. 85, 755– 778. 10.3233/JAD-210523. 34864660 · DOI · Paper page
  22. [24]Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17. 10.1016/j.cell.2017.05.018. 28602351 · DOI · Paper page
  23. [27]De Schepper S, Ge JZ, Crowley G, Ferreira LSS, Garceau D, Toomey CE, Sokolova D, Rueda-Carrasco J, Shin S-H, Kim J-S, (2023). Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease. Nat. Neurosci 26, 406– 415. 10.1038/s41593-023-01257-z. 36747024 PMC9991912 · DOI · Paper page
  24. [28]Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Ru€be CE, Walter J, Heneka MT, Hartmann T, (2012). TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J. Immunol 188, 1098– 1107. 10.4049/jimmunol.1101121. 22198949 · DOI · Paper page
  25. [31]Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, (2013). Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24, 213– 228. 10.1016/j.ccr.2013.06.014. 23911236 PMC3753022 · DOI
  26. [34]Schoch KM, Ezerskiy LA, Morhaus MM, Bannon RN, Sauerbeck AD, Shabsovich M, Jafar-Nejad P, Rigo F, and Miller TM (2021). Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice. Proc. Natl. Acad. Sci. USA 118, e2100356118. 10.1073/pnas.2100356118. PMC8271763 34187891 · DOI · Paper page
  27. [37]Garcia SN, Guedes RC, and Marques MM (2019). Unlocking the potential of HK2 in cancer metabolism and therapeutics. Curr. Med. Chem 26, 7285– 7322. 10.2174/0929867326666181213092652. 30543165 · DOI
  28. [38]Cervantes-Madrid D, Romero Y, and Dueñas-González A. (2015). Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy. BioMed Res. Int 2015, 690492. 10.1155/2015/690492. PMC4575731 26425550 · DOI
  29. [41]Thawkar BS, and Kaur G. (2019). Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. J. Neuroimmunol 326, 62– 74. 10.1016/j.jneuroim.2018.11.010. 30502599 · DOI
  30. [43]Bianco A, Antonacci Y, and Liguori M. (2023). Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities. Int. J. Mol. Sci 24, 6354. 10.3390/ijms24076354. 37047320 PMC10093984 · DOI
  31. [44]Zucker I, and Prendergast BJ (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11, 32. 10.1186/s13293-020-00308-5. 32503637 PMC7275616 · DOI · Paper page
  32. [45]Nath K, Guo L, Nancolas B, Nelson DS, Shestov AA, Lee S-C, Roman J, Zhou R, Leeper DB, Halestrap AP, (2016). Mechanism of antineoplastic activity of lonidamine. Biochim. Biophys. Acta 1866, 151– 162. 10.1016/j.bbcan.2016.08.001. 27497601 PMC5138080 · DOI
  33. [46]Bhutia YD, Babu E, and Ganapathy V. (2016). Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine. Biochem. J 473, 1503– 1506. 10.1042/BCJ20160068. 27234586 PMC4888454 · DOI
  34. [47]Wang P, Henning SM, and Heber D. (2010). Limitations of MTT and MTS-based assays for measurement of antiproliferative activity of green tea polyphenols. PLoS One 5, e10202. 10.1371/journal.pone.0010202. PMC2855713 20419137 · DOI
  35. [48]Gao C, Jiang J, Tan Y, and Chen S. (2023). Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct. Targeted Ther. 8, 359. 10.1038/s41392-023-01588-0. PMC10514343 37735487 · DOI · Paper page
  36. [49]Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, (2017). Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355– 361. 10.1038/nature25158. 29293211 · DOI · Paper page
  37. [50]Zipp F, Bittner S, and Schafer DP (2023). Cytokines as emerging regulators of central nervous system synapses. Immunity 56, 914– 925. 10.1016/j.immuni.2023.04.011. 37163992 PMC10233069 · DOI
  38. [51]Guo D, Tong Y, Jiang X, Meng Y, Jiang H, Du L, Wu Q, Li S, Luo S, Li M, (2022). Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IKBα. Cell Metabol. 34, 1312– 1324.e6. 10.1016/j.cmet.2022.08.002. 36007522 · DOI
  39. [52]Demarquoy J, and Le Borgne F. (2015). Crosstalk between mitochondria and peroxisomes. World J. Biol. Chem 6, 301– 309. 10.4331/wjbc.v6.i4.301. 26629313 PMC4657118 · DOI
  40. [53]Lin J, Fang W, Xiang Z, Wang Q, Cheng H, Chen S, Fang J, Liu J, Wang Q, Lu Z, and Ma L. (2023). Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion. Front. Immunol 14, 1189953. 10.3389/fimmu.2023.1189953. PMC10291184 37377974 · DOI
  41. [54]Baik SH, Kang S, Lee W, Choi H, Chung S, Kim J-I, and Mook-Jung I. (2019). A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer’s Disease. Cell Metabol. 30, 493– 507.e6. 10.1016/j.cmet.2019.06.005. 31257151 · DOI · Paper page
  42. [55]Lynch MA (2020). Can the emerging field of immunometabolism provide insights into neuroinflammation? Prog. Neurobiol 184, 101719. 10.1016/j.pneurobio.2019.101719. 31704314 · DOI
  43. [57]Hinrichsen F, Hamm J, Westermann M, Schröder L, Shima K, Mishra N, Walker A, Sommer N, Klischies K, Prasse D, (2021). Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis. Cell Metabol. 33, 2355– 2366.e8. 10.1016/j.cmet.2021.11.004. 34847376 · DOI
  44. [61]Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, (2008). Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat. Biotechnol 26, 317– 325. 10.1038/nbt1385. 18278033 · DOI · Paper page

Authors
Codocedo, J. F., Mera-Reina, C., Bor-Chian Lin, P., Fallen, P. B., Puntambekar, S. S., Casali, B. T., Jury-Garfe, N., Martinez, P., Lasagna-Reeves, C. A., & Landreth, G. E.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
Landreth, Gary E.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2024-07
Volume
43
Issue
7
Pages
114488
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2024.114488
PMC
PMC11398604
OpenAlex
W4400606023
Cited by
52
References
61
Citations by year
2026: 36 · 2025: 15 · 2024: 1
FWCI
8.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (RF1AG068400)
  • CTSI (EPAR1536)
  • University of Illinois College of Medicine
  • School of Medicine, Indiana University (P30 CA082709)
  • BrightFocus Foundation (A20201166F)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, microglia, immunometabolism, hexokinase 2, gene dosage, neuroinflammation, glycolysis, NF-κB signaling, IkBα, haploinsufficiency, 5xFAD mice, mitochondrial dysfunction, microglial activation
MeSH terms
NF-KappaB Inhibitor alpha, Alzheimer Disease, Animals, Brain, Glycolysis, Hexokinase, Humans, Inflammation, Mice, Transgenic, Mitochondria, Signal Transduction, NF-kappa B, Microglia, Disease Progression, Gene Dosage, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review