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Cited by 11Hearing, Cochlea, Tinnitus, GeneticsAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

APOE4 impairs macrophage lipophagy and promotes demyelination of spiral ganglion neurons in mouse cochleae

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Chen, Junru, Chen, Haibing, Wei, Qinjun, Lu, Yajie, Wang, Tianming, Pang, Xiuhong, Xing, Guangqian, Chen, Zhibin +2 more·2025·Cell Death Discovery
DOI 10.1038/s41420-025-02454-4PMC PMC12012174
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Abstract

The ApoE-ε4 gene is a well-established genetic risk factor for neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis, which are characterized by axonal demyelination in the central nervous system. Recent studies have implicated ApoE-ε4 in age-related hearing loss (ARHL), suggesting a potential role of APOE4 isoform in peripheral nervous system degeneration. However, the role of APOE4 in ARHL are still unclear. In this study, we explored the potential role of APOE4 in axonal demyelination of spiral ganglion neurons (SGNs). ApoE-ε4/ε4 (APOE4) and ApoE-ε3/ε3 (APOE3) mice were used to characterize SGNs. The effect of APOE4 on phagocytosis and autophagy as well as intracellular cholesterol level was evaluated in resident cochlear macrophages (RCMs) and mouse bone marrow-derived macrophages (BMDMs). The results showed that significant axonal demyelination was observed in SGNs of 10-month-old APOE4 mice, accompanied by the presence of myelin debris engulfed by RCMs. Meanwhile, inhibited phagocytosis of myelin debris and impaired lipophagy were detected in APOE4 RCMs and APOE4 BMDMs with an aberrant accumulation of lipid droplets (LDs), which could be reversed by trehalose treatment. This study provided a deep insight into the pathogenesis of APOE4-induced axonal demyelination of SGNs associated with the impaired lipophagy in RCMs, which helped to elucidate the underlying mechanism of ApoE-ε4 in ARHL.

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  • E4 is associated with an impaired phagocytic response in microglia compared to E3 and E2.

    “in which E4 is associated with an impaired phagocytic response and dysregulated immuno-metabolic function compared to E3 and E2 microglia”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Chen et al., 2025

    The Introduction reports that some studies found reduced phagocytic efficacy in APOE4 human microglia-like cells and recognizes disrupted microglial cholesterol metabolism. The Results show reduced myelin-debris uptake in APOE4 macrophages compared with APOE3 controls, but the paper does not establish the claimed comparison with E2 microglia. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • E4 is associated with dysregulated immuno-metabolic function in microglia compared to E3 and E2.

    “in which E4 is associated with an impaired phagocytic response and dysregulated immuno-metabolic function compared to E3 and E2 microglia”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Chen et al., 2025

    The Introduction (page unavailable) reports impaired phagocytosis and disrupted cholesterol metabolism in APOE4 microglia. The Results and Discussion (pages unavailable) show reduced myelin-debris phagocytosis and altered lipid handling relative to APOE3, but those experiments used mouse macrophages, not microglia. The paper does not establish the claimed comparison with APOE2 microglia. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Microglia exhibit distinct APOE-genotype dependent transcriptional diversity.

    “They also exhibit distinct APOE-genotype dependent transcriptional diversity”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Chen et al., 2025

    The Introduction discusses APOE-related changes in microglial lipid metabolism and phagocytosis, but does not describe genotype-dependent transcriptional diversity. The Methods describe gene-expression measurements in whole cochleae and bone-marrow-derived macrophages, not transcriptional profiling of microglia. Searches for microglial transcriptional diversity and transcriptomic profiling found no passage addressing the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 43

  1. [3]Chang TY, Yamauchi Y, Hasan MT, Chang C. Cellular cholesterol homeostasis and Alzheimer’s disease: Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer’s Disease. J Lipid Res. 2017;58:2239–54. 28298292 PMC5711498 · DOI · Paper page
  2. [5]Slade K, Plack CJ, Nuttall HE. The Effects of Age-Related Hearing Loss on the Brain and Cognitive Function. Trends Neurosci. 2020;43:810–21. 32826080 · DOI
  3. [6]Kurniawan C, Westendorp RGJ, de Craen AJM, Gussekloo J, de Laat J, van Exel E. Gene dose of apolipoprotein E and age-related hearing loss. Neurobiol Aging. 2012;33:2230.e7–2230.e12. 22542837 · DOI
  4. [7]Chai R, Li GL, Wang J, Zou J. Hearing Loss: Reestablish the Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells. Neural Plast. 2017;2017:1807581. 28316840 PMC5337833 · DOI
  5. [8]Liberman MC, Liberman LD, Maison SF. Chronic Conductive Hearing Loss Leads to Cochlear Degeneration. PLoS One. 2015;10:e0142341. 26580411 PMC4651495 · DOI
  6. [9]Griffin JW, George R, Lobato C, Tyor WR, Li CY, Glass JD. Macrophage responses and myelin clearance during Wallerian degeneration: relevance to immune-mediated demyelination. J Neuroimmunol. 1992;40:153–65. 1430148 · DOI
  7. [10]Kent SA, Miron VE. Microglia regulation of central nervous system myelin health and regeneration. Nat Rev Immunol. 2024;24:49–63. 37452201 · DOI · Paper page
  8. [11]Maitre M, Jeltsch-David H, Okechukwu NG, Klein C, Patte-Mensah C, Mensah-Nyagan AG. Myelin in Alzheimer’s disease: culprit or bystander? Acta Neuropathol Commun. 2023;11:56. 37004127 PMC10067200 · DOI · Paper page
  9. [13]Wang N, Wang M, Jeevaratnam S, Rosenberg C, Ikezu TC, Shue F, et al. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination. Mol Neurodegener. 2022;17:75. 36419137 PMC9682675 · DOI · Paper page
  10. [17]Young JE, Jayadev S. Neighborhood matters: Altered lipid metabolism in APOE4 microglia causes problems for neurons. Cell Stem Cell. 2022;29:1159–60. 35931027 PMC12495995 · DOI · Paper page
  11. [18]Wang C, Lu J, Sha X, Qiu Y, Chen H, Yu Z. TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia. Exp Mol Med. 2023;55:347–63. 36720919 PMC9981624 · DOI · Paper page
  12. [19]Muth C, Hartmann A, Sepulveda-Falla D, Glatzel M, Krasemann S. Phagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro. Front Cell Neurosci. 2019;13:181. 31130847 PMC6509203 · DOI
  13. [20]Avraham O, Feng R, Ewan EE, Rustenhoven J, Zhao G, Cavalli V. Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair. eLife. 2021;10:e68457. 34586065 PMC8480984 · DOI
  14. [21]Wu S, Romero-Ramírez L, Mey J. Retinoic acid increases phagocytosis of myelin by macrophages. J Cell Physiol. 2021;236:3929–45. 33165955 PMC7984038 · DOI
  15. [22]Grajchen E, Wouters E, van de Haterd B, Haidar M, Hardonnière K, Dierckx T, et al. CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation. J Neuroinflammation. 2020;17:224. 32718316 PMC7384221 · DOI
  16. [23]Robichaud S, Fairman G, Vijithakumar V, Mak E, Cook DP, Pelletier AR, et al. Identification of novel lipid droplet factors that regulate lipophagy and cholesterol efflux in macrophage foam cells. Autophagy. 2021;17:3671–89. 33590792 PMC8632324 · DOI
  17. [24]Shin DW. Lipophagy: Molecular Mechanisms and Implications in Metabolic Disorders. Mol Cells. 2020;43:686–93. 32624503 PMC7468585
  18. [25]Schott MB, Weller SG, Schulze RJ, Krueger EW, Drizyte-Miller K, Casey CA, et al. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. J Cell Biol. 2019;218:3320–35. 31391210 PMC6781454 · DOI · Paper page
  19. [26]Zhou T, Zheng Y, Sun L, Badea SR, Jin Y, Liu Y, et al. Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury. Nat Neurosci. 2019;22:421–35. 30664769 PMC6913093 · DOI
  20. [27]Plemel JR, Michaels NJ, Weishaupt N, Caprariello AV, Keough MB, Rogers JA, et al. Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy. Glia. 2018;66:327–47. 29068088 · DOI · Paper page
  21. [28]He W, Yu J, Sun Y, Kong W. Macrophages in Noise-Exposed Cochlea: Changes, Regulation and the Potential Role. Aging Dis. 2020;11:191–9. 32010492 PMC6961779 · DOI
  22. [29]Parney IF, Waldron JS, Parsa AT. Flow cytometry and in vitro analysis of human glioma–associated macrophages: Laboratory investigation. J Neurosurg. 2009;110:572–82. 19199469 PMC3064468 · DOI
  23. [31]Haidar M, Loix M, Vanherle S, Dierckx T, Vangansewinkel T, Gervois P, et al. Targeting lipophagy in macrophages improves repair in multiple sclerosis. Autophagy. 2022;18:2697–710. PMC9629102 35282773
  24. [32]McBrayer M, Nixon RA. Lysosome and Calcium Dysregulation in Alzheimer’s Disease – Partners in Crime. Biochem Soc Trans. 2013;41:1495–502. PMC3960943 24256243
  25. [33]Mahapatra KK, Mishra SR, Behera BP, Patil S, Gewirtz DA, Bhutia SK. The lysosome as an imperative regulator of autophagy and cell death. Cell Mol Life Sci 2021;78:7435–49. 34716768 PMC11071813 · DOI
  26. [34]Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): A multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther. 2022;233:108024. 34673115
  27. [35]Jiang P, Mizushima N. LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods. 2015;75:13–8. 25484342
  28. [36]DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, et al. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9:ra21. 26905426 PMC4816640 · DOI · Paper page
  29. [37]Mayer AL, Higgins CB, Heitmeier MR, Kraft TE, Qian X, Crowley JR, et al. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6:38586. 27922102 PMC5138640 · DOI
  30. [38]Schmidt S, Joost HG, Schürmann A. GLUT8, the enigmatic intracellular hexose transporter. Am J Physiol Endocrinol Metab. 2009;296:E614–618. 19176349 · DOI
  31. [39]Rusmini P, Cortese K, Crippa V, Cristofani R, Cicardi ME, Ferrari V, et al. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2018;15:631–51. PMC6526812 30335591
  32. [40]Gopar-Cuevas Y, Saucedo-Cardenas O, Loera-Arias MJ, Montes-de-Oca-Luna R, Rodriguez-Rocha H, Garcia-Garcia A. Metformin and Trehalose-Modulated Autophagy Exerts a Neurotherapeutic Effect on Parkinsonʼs Disease. Mol Neurobiol. 2023;60:7253–73. 37542649
  33. [41]Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging. 2023;3:275–96. PMC10154214 37118426
  34. [42]Zhuang H, Li Q, Sun C, Xu D, Gan G, Zhang C, et al. Voluntary wheel exercise ameliorates cognitive impairment, hippocampal neurodegeneration and microglial abnormalities preceded by demyelination in a male mouse model of noise-induced hearing loss. Brain Behav Immun. 2023;114:325–48. 37683962
  35. [44]Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21:7533. PMC7589539 33066029
  36. [45]Huebbe P, Rimbach G. Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors. Ageing Res Rev. 2017;37:146–61. 28647612 · DOI
  37. [47]Quick JD, Silva C, Wong JH, Lim KL, Reynolds R, Barron AM, et al. Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration. J Neuroinflammation. 2023;20:185. 37543564 PMC10403868 · DOI · Paper page
  38. [49]Jeong SJ, Stitham J, Evans TD, Zhang X, Rodriguez-Velez A, Yeh YS, et al. Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response. Autophagy. 2021:17:3740–52. PMC8632292 33706671
  39. [50]Pupyshev AB, Klyushnik TP, Akopyan AA, Singh SK, Tikhonova MA. Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential. Pharmacol Res. 2022;183:106373. 35907433 · DOI
  40. [51]Duncan ID, Radcliff AB, Heidari M, Kidd G, August BK, Wierenga LA. The adult oligodendrocyte can participate in remyelination. Proc Natl Acad Sci USA. 2018;115:E11807–16. 30487224 PMC6294923 · DOI · Paper page
  41. [52]Liu L, Du X, Yang Q, Li M, Ran Q, Liu Q, et al. Ginsenoside Rg1 promotes remyelination and functional recovery in demyelinating disease by enhancing oligodendrocyte precursor cells-mediated myelin repair. Phytomedicine. 2022;106:154309. 35994846 · DOI
  42. [53]Okano T, Nakagawa T, Kita T, Kada S, Yoshimoto M, Nakahata T, et al. Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea. J Neurosci Res. 2008;86:1758–67. 18253944 · DOI
  43. [54]de Ferreira PMP, de Sousa RWR, de Ferreira JRO, Militão GCG, Bezerra DP. Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms. Pharm Res. 2021;168:105582. 33775862 · DOI

Cited by

Sorted by citations

Authors
Chen, J., Chen, H., Wei, Q., Lu, Y., Wang, T., Pang, X., Xing, G., Chen, Z., Cao, X., & Yao, J.
Affiliations
  • Nanjing Medical University (CN)
  • Jiangsu Province Hospital (CN)
  • Nanjing Jiangning Hospital (CN)
  • The Affiliated Taizhou People's Hospital of Nanjing Medical University (CN)
Corresponding author
  • Chen, Zhibin
  • Cao, Xin
  • Yao, Jun
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2025-04-21
Volume
11
Issue
1
Pages
190-190
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/s41420-025-02454-4
PMC
PMC12012174
OpenAlex
W4409628424
Cited by
11
References
11
Citations by year
2026: 6 · 2025: 5
FWCI
6.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82071052, 82200642, 32070587)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
APOE ε4, age-related hearing loss, spiral ganglion neurons, axonal demyelination, lipophagy, phagocytosis, autophagy, lipid droplets, intracellular cholesterol, trehalose, myelin debris, APOE3

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