The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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?
The present work substantially advances the field by focusing specifically on astrocyte responses in the context of FH, a mechanism that remains insufficiently explored.
“Although previous studies have examined the effects of LDL on glial cells (Chen et al. 2024; Niu et al. 2025), the present work substantially advances the field by focusing specifically on astrocyte responses in the context of FH, a mechanism that remains insufficiently explored.”
From LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models (2026) · cites this paper as Chen et al. 2024
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · cited 1×
“These findings align with previous studies on aging and white matter damage, where lipid-rich myelin debris induces microglia to produce large amounts of pro-inflammatory cytokines [42].”
ResultTREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.007 · Cited by 745
The pro-remyelination properties of microglia in the central nervous system
Lloyd, A. F., & Miron, V. E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0184-2 · Cited by 381
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
Yang, S., Qin, C., Hu, Z.-W., Zhou, L.-Q., Yu, H.-H., Chen, M., Bosco, D. B., Wang, W., Wu, L.-J., & Tian, D.-S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105290 · Cited by 232
Self-citationApaijai, N., Moisescu, D. M., Palee, S., McSweeney, C. M., Saiyasit, N., Maneechote, C., Boonnag, C., Chattipakorn, N., & Chattipakorn, S. C. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.010838 · Cited by 90
Flagged first, then by citations
Research works printed but not linked: 39
- Jarius S, Paul F, Weinshenker BG, Levy M, Kim HJ, Wildemann B. Neuromyelitis optica. Nat Rev Dis Primers 2020, 6: 85. · DOI
- Papp V, Magyari M, Aktas O, Berger T, Broadley SA, Cabre P. Worldwide incidence and prevalence of neuromyelitis optica: A systematic review. Neurology 2021, 96: 59–77. · DOI
- Wu Y, Zhong L, Geng J. Neuromyelitis optica spectrum disorder: Pathogenesis, treatment, and experimental models. Mult Scler Relat Disord 2019, 27: 412–418. · DOI
- Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012, 11: 535–544. · DOI
- Chen T, Lennon VA, Liu YU, Bosco DB, Li Y, Yi MH, et al. Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion. J Clin Invest 2020, 130: 4025–4038.
- Moinfar Z, Zamvil SS. Microglia complement astrocytes in neuromyelitis optica. J Clin Invest 2020, 130: 3961–3964.
- Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 2007, 69: 2221–2231. · DOI
- Tradtrantip L, Yao X, Su T, Smith AJ, Verkman AS. Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol 2017, 134: 35–44. · DOI · Paper page
- da Silva APB, Souza DG, Souza DO, Machado DC, Sato DK. Role of glutamatergic excitotoxicity in neuromyelitis optica spectrum disorders. Front Cell Neurosci 2019, 13: 142. · DOI
- Shimizu F, Sano Y, Takahashi T, Haruki H, Saito K, Koga M, et al. Sera from neuromyelitis optica patients disrupt the blood-brain barrier. J Neurol Neurosurg Psychiatry 2012, 83: 288–297. · DOI
- Takeshita Y, Fujikawa S, Serizawa K, Fujisawa M, Matsuo K, Nemoto J, et al. New BBB model reveals that IL-6 blockade suppressed the BBB disorder, preventing onset of NMOSD. Neurol Neuroimmunol Neuroinflamm 2021, 8: e1076. · DOI
- Pineda-Torra I, Siddique S, Waddington KE, Farrell R, Jury EC. Disrupted lipid metabolism in multiple sclerosis: A role for liver X receptors? Front Endocrinol (Lausanne) 2021, 12: 639757. · DOI
- Giudetti AM, Romano A, Lavecchia AM, Gaetani S. The role of brain cholesterol and its oxidized products in alzheimer’s disease. Curr Alzheimer Res 2016, 13: 198–205. · DOI
- Cho EB, Cho HJ, Choi M, Seok JM, Shin HY, Kim BJ, et al. Low high-density lipoprotein cholesterol and high triglycerides lipid profile in neuromyelitis optica spectrum disorder: Associations with disease activity and disability. Mult Scler Relat Disord 2020, 40: 101981. · DOI
- Chen T, Bosco DB, Ying Y, Tian DS, Wu LJ. The emerging role of microglia in neuromyelitis optica. Front Immunol 2021, 12: 616301. · DOI
- Yu LE, Lai CL, Lee CT, Wang JY. Highly electronegative low-density lipoprotein L5 evokes microglial activation and creates a neuroinflammatory stress via Toll-like receptor 4 signaling. J Neurochem 2017, 142: 231–245. · DOI
- Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015, 85: 177–189. · DOI · Paper page
- Ma X, Qin C, Chen M, Yu HH, Chu YH, Chen TJ, et al. Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder. J Neuroinflammation 2021, 18: 201. · DOI · Paper page
- Wang Z, Guo W, Liu Y, Gong Y, Ding X, Shi K, et al. Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes. Brain Behav Immun 2017, 65: 173–182. · DOI
- Xu X, Gao W, Cheng S, Yin D, Li F, Wu Y, et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation 2017, 14: 167. · DOI
- Luong TN, Carlisle HJ, Southwell A, Patterson PH. Assessment of motor balance and coordination in mice using the balance beam. J Vis Exp 2011, 2011: 2376.
- Baydyuk M, Cha DS, Hu J, Yamazaki R, Miller EM, Smith VN, et al. Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye. Proc Natl Acad Sci U S A 2019, 116: 14290–14299. · DOI
- Zhang H, Yang S, Chen M, Tian DS, Qin C. Isolation of mouse primary microglia by magnetic-activated cell sorting in animal models of demyelination. J Vis Exp 2022, https://doi.org/10.3791/63511. · DOI
- Shi L, Sun Z, Su W, Xu F, Xie D, Zhang Q, et al. Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity 2021, 54: 1527–1542. · DOI
- Yang J, Cheng X, Shen J, Xie B, Zhao X, Zhang Z, et al. A novel approach for amplification and purification of mouse oligodendrocyte progenitor cells. Front Cell Neurosci 2016, 10: 203. · DOI
- Shen K, Reichelt M, Kyauk RV, Ngu H, Shen YA, Foreman O, et al. Multiple sclerosis risk gene Mertk is required for microglial activation and subsequent remyelination. Cell Rep 2021, 34: 108835. · DOI · Paper page
- Kajimoto M, Nuri M, Sleasman JR, Charette KA, Nelson BR, Portman MA. Inhaled nitric oxide reduces injury and microglia activation in porcine hippocampus after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2021, 161: e485–e498. · DOI
- Qin C, Chen M, Dong MH, Yang S, Zhang H, You YF, et al. Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders. Brain 2023, 2023: 321.
- Wang JK, Li Y, Zhao XL, Liu YB, Tan J, Xing YY, et al. Ablation of plasma prekallikrein decreases low-density lipoprotein cholesterol by stabilizing low-density lipoprotein receptor and protects against atherosclerosis. Circulation 2022, 145: 675–687. · DOI
- Qi Z, Hu L, Zhang J, Yang W, Liu X, Jia D, et al. PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36. Circulation 2021, 143: 45–61. · DOI · Paper page
- Dong F, Liu D, Jiang F, Liu Y, Wu X, Qu X, et al. Conditional deletion of Foxg1 alleviates demyelination and facilitates remyelination via the Wnt signaling pathway in cuprizone-induced demyelinated mice. Neurosci Bull 2021, 37: 15–30. · DOI
- Li W, Liu J, Tan W, Zhou Y. The role and mechanisms of Microglia in Neuromyelitis Optica Spectrum Disorders. Int J Med Sci 2021, 18: 3059–3065. · DOI
- Jang J, Nam Y, Choi Y, Shin NY, An JY, Ahn KJ, et al. Paramagnetic rims in multiple sclerosis and neuromyelitis optica spectrum disorder: A quantitative susceptibility mapping study with 3-T MRI. J Clin Neurol 2020, 16: 562–572. · DOI
- Niiranen M, Kontkanen A, Jääskeläinen O, Tertsunen HM, Selander T, Hartikainen P, et al. Serum GFAP and NfL levels in benign relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2021, 56: 103280. · DOI · Paper page
- Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med 2019, 25: 277–283. · DOI · Paper page
- Zhou LQ, Dong MH, Hu ZW, Tang Y, Chu YH, Chen M, et al. Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid. Proc Natl Acad Sci U S A 2023, 120: e2209990120. · DOI
- Colombo A, Dinkel L, Müller SA, Sebastian Monasor L, Schifferer M, Cantuti-Castelvetri L, et al. Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nat Commun 2021, 12: 1158. · DOI
- Artyomov MN, Van den Bossche J. Immunometabolism in the single-cell era. Cell Metab 2020, 32: 710–725. · DOI
- Negrotto L, Farez MF, Correale J. Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. JAMA Neurol 2016, 73: 520–528. · DOI · Paper page
Cited by
Sorted by citations
Baumart, G. J., Rodrigues, M. S., Sholl, J. N., de Sousa, A. C., Weber, A. F., Costa‐Beber, L. C., Farias, H. R., Costa, M. V., Peres, A. M., de Camargo, P. R., et al. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70403 · Cited by 2
Metadata
- Authors
- Chen, M., Chu, Y.-H., Yu, W.-X., You, Y.-F., Tang, Y., Pang, X.-W., Zhang, H., Shang, K., Deng, G., Zhou, L.-Q., Yang, S., Wang, W., Xiao, J., Tian, D.-S., & Qin, C.
- ORCID
- Qin, Chuan
- Venue
- Neuroscience Bulletin
- Published
- 2024-01-16
- Volume
- 40
- Issue
- 8
- Pages
- 1104-1114
- ISSN
- 1673-7067
- 1995-8218
- PMC
- PMC11306683
- Cited by
- 18
- References
- 5
- Language
- en
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
