Type I Interferon Response‐related Microglial Mef2c Deregulation at the Onset of Alzheimer's Pathology in 5×FAD Mice
Open accessAbstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder with multifactorial etiology. The role of microglia in the pathogenesis of AD has been increasingly recognized in recent years; however, the detailed mechanisms shaping microglial phenotypes in AD-relevant pathological settings remain largely unresolved. Myocyte-specific enhancer factor 2C (Mef2C) is a transcription factor with versatile functions. Recent studies have attributed aging-related microglial changes to type I interferon (IFN-I)-associated Mef2C deregulation. In view of the close relationship between brain aging and AD, it is of great interest to determine microglial Mef2C changes in AD-related conditions. In this study, we have found that suppressed Mef2C nuclear translocation was an early and prominent microglial phenotype in a mouse model of brain amyloidosis (5×FAD mice), which exacerbated with age. Echoing the early Mef2C deregulation and its association with microglial activation, transcriptional data showed elicited IFN-I response in microglia from young 5×FAD mice. Amyloid beta 42 (Aβ42) in its oligomeric forms promoted Mef2C deregulation in microglia on acute organotypic brain slices with augmented microglial activation and synapse elimination via microglial phagocytosis. Importantly, these oligomeric Aβ42-mediated microglial changes were substantially attenuated by blocking IFN-I signaling. The simplest interpretation of the results is that Mef2C, concurring with activated IFN-I signaling, constitutes early microglial changes in AD-related conditions. In addition to the potential contribution of Mef2C deregulation to the development of microglial phenotypes in AD, Mef2C suppression in microglia may serve as a potential mechanistic pathway linking brain aging and AD.
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
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?
Reduced neuronal MEF2C levels, due to neuroinflammation or aging, impair synaptic maintenance, subsequently leading to increased synapse loss.
“Previous studies have shown that reduced neuronal MEF2C levels, due to neuroinflammation or aging, impair synaptic maintenance, subsequently leading to increased synapse loss [45, 46].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [46]
The Results report reduced microglial Mef2C nuclear translocation alongside increased microglial engulfment of synaptic material in 5×FAD mice. The Discussion notes that neuronal Mef2C affects synaptic transmission, but says whether it is affected in AD neurons remains for future study. The paper does not establish that neuroinflammation or aging reduces neuronal MEF2C, impairing synaptic maintenance and causing synapse loss. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn a 5xFAD mouse model of Alzheimer's disease, decreased microglial MEF2C nuclear translocation contributes to chronic neuroinflammation, which exacerbates neurodegeneration.
“In a 5xFAD mouse model of Alzheimer's disease, decreased microglial MEF2C nuclear translocation contributes to chronic neuroinflammation, which exacerbates neurodegeneration [46].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [46]
The Results section reports decreased nuclear Mef2C in microglia from 5×FAD mice, alongside signs of microglial activation. The Discussion says these changes are associated but explicitly states that the study cannot establish whether Mef2C deregulation causes pro-inflammatory activation. It does not establish the claimed chain from reduced nuclear translocation to chronic neuroinflammation and worsened neurodegeneration (page numbers unavailable). (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn later stages of Alzheimer's disease, reducing PU.1 activity while increasing MEF2C activity inhibits harmful inflammation and supports neuroprotective microglial functions.
“in the later stages, it might be beneficial to reduce PU.1 activity while increasing MEF2C activity to inhibit harmful inflammation and support neuroprotective microglial functions”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [46]
The Discussion (page unavailable) associates reduced microglial MEF2C activation with inflammatory changes in 5×FAD mice, but explicitly says the study cannot establish a cause-and-effect relationship. The Results concern early AD pathology, not a later-stage intervention; the cited passages do not support reducing PU.1 activity or show that increasing MEF2C produces neuroprotective functions. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMEF2C functions as a counterbalance by suppressing excessive pro-inflammatory responses.
“MEF2C functions as a counterbalance by suppressing excessive pro‐inflammatory responses”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [46]
The Discussion (page not provided) says Mef2C-deficient microglia are more sensitive to inflammatory mediator-induced pro-inflammatory changes, consistent with a counterbalancing role in microglia. But the paper describes its own finding as a potential role for Mef2C in microglial activation; it does not establish the broader, definitive claim that MEF2C suppresses excessive pro-inflammatory responses. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPU.1, IRF8, and BHLHE40/41 regulate multiple downstream targets that orchestrate microglial immune response functions, including phagocytosis, cytokine production, and inflammatory signaling.
“PU.1, IRF8, and BHLHE40/41 regulates multiple downstream targets that orchestrate microglial immune response functions, including phagocytosis, cytokine production, and inflammatory signaling”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [46]
The Results and Discussion describe IFN-I signaling, Mef2C deregulation, and microglial phagocytosis, but do not connect the claimed functions to PU.1, IRF8, or BHLHE40/41. Searches for those factors and their proposed downstream targets found no passage addressing that regulatory claim. Page numbers were not available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · see citing works
Aβ Oligomers – a decade of discovery
Walsh, D. M., & Selkoe, D. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04426.x · Cited by 1,938 · see citing works
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · see citing works
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
Self-citationSpangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
TREM2 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 · see citing works
Eimer, W. A., & Vassar, R. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-2 · Cited by 425 · cited 2× · see citing works
“4 5×FAD mice at 3–4 months old demonstrate mild brain Aβ deposition and neuroinflammation with modest cognitive defects mimicking earlystage AD while 5×FAD mice at the older age have heavy Aβ burden and severely impaired cognition (Beck et al., 2016; Eimer and Vassar, 2013; Tian et al., 2019).”
BackgroundBrain aging, Alzheimer's disease, and mitochondria
Swerdlow, R. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.012 · Cited by 306 · cited 2× · see citing works
“In view of the close relationship between brain aging and AD (Deak et al., 2016; Swerdlow, 2011), pathological changes in the aging brain are informative for our understanding of AD pathogenesis.”
BackgroundNeurons produce type I interferon during viral encephalitis
Delhaye, S., Paul, S., Blakqori, G., Minet, M., Weber, F., Staeheli, P., & Michiels, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602460103 · Cited by 266 · see citing works
Deczkowska, A., Matcovitch-Natan, O., Tsitsou-Kampeli, A., Ben-Hamo, S., Dvir-Szternfeld, R., Spinrad, A., Singer, O., David, E., Winter, D. R., Smith, L. K., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00769-0 · Cited by 260 · see citing works
Immune reactive cells in senile plaques and cognitive decline in Alzheimer’s disease
Vehmas, A. K., Kawas, C. H., Stewart, W. F., & Troncoso, J. C. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00090-8 · Cited by 230 · see citing works
Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
Inflammasome-mediated innate immunity in Alzheimer’s disease
Venegas, C., & Heneka, M. T. (2019) · The FASEB Journal · doi:10.1096/fj.201900439 · Cited by 93 · see citing works
Flagged first, then by citations
Research works printed but not linked: 56
- Anderson CM,, 2015. Myocyte enhancer factor 2C function in skeletal muscle is required for normal growth and glucose metabolism in mice. Skelet. Muscle 5, 7. 25789156 PMC4364460
- Andoh M,, 2019. Exercise reverses behavioral and synaptic abnormalities after maternal inflammation. Cell Rep. 27 (2817–2825), e5. 31167129
- Aw E,, 2020. Microglial responses to peripheral type 1 interferon. J. Neuroinflammation 17, 340. 33183319 PMC7659169
- Baruch K,, 2013. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc. Natl. Acad. Sci. U. S. A 110, 2264– 2269. 23335631 PMC3568380
- Beck SJ,, 2016. Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease. Nat. Commun. 7, 11483. 27151236 PMC5494197
- Ben-Yehuda H,, 2020. Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress. Mol. Psychiatry 25, 1050– 1067. 31772304 PMC7192855
- Bordt EA,, 2020. Isolation of microglia from mouse or human tissue. STAR Protoc 1. PMC7416840 32783030
- Brown FC,, 2018. MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. Cancer Discov 8, 478– 497. 29431698 PMC5882571
- Colonna M, Butovsky O, 2017. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol 35, 441– 468. 28226226 PMC8167938
- Cummings J, 2019. The role of biomarkers in Alzheimer’s disease drug development. Adv. Exp. Med. Biol 1118, 29– 61. 30747416 PMC6750734
- Deak F,, 2016. Recent developments in understanding brain aging: implications for Alzheimer’s disease and vascular cognitive impairment. J. Gerontol. A Biol. Sci. Med. Sci 71, 13– 20. 26590911 PMC4851715
- Dong C,, 2017. Myocyte enhancer factor 2C and its directly-interacting proteins: a review. Prog. Biophys. Mol. Biol 126, 22– 30. 28163053
- Dubois B,, 2010. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9, 1118– 1127. 20934914
- Fitzgerald-Bocarsly P, Feng D, 2007. The role of type I interferon production by dendritic cells in host defense. Biochimie 89, 843– 855. 17544561 PMC2752847
- Franco-Bocanegra DK,, 2019. Microglial motility in Alzheimer’s disease and after Abeta42 immunotherapy: a human post-mortem study. Acta Neuropathol Commun 7, 174. 31703599 PMC6842157
- Fu W,, 2006. MEF2C mediates the activation induced cell death (AICD) of macrophages. Cell Res 16, 559– 565. 16775627
- Gorle N, Vandenbroucke RE, 2019. Interferons: a molecular switch between damage and repair in ageing and Alzheimer’s disease. Mech. Ageing Dev 183, 111148. 31541624
- Harrington AJ,, 2016. MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife 5. PMC5094851 27779093
- Heneka MT,, 2015. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14, 388– 405. 25792098 PMC5909703
- Kong NR,, 2016. MEF2C and EBF1 co-regulate B cell-specific transcription. PLoS Genet 12, e1005845. 26900922 PMC4762780
- Kongsui R,, 2014. Quantitative assessment of microglial morphology and density reveals remarkable consistency in the distribution and morphology of cells within the healthy prefrontal cortex of the rat. J. Neuroinflammation 11, 182. 25343964 PMC4213482
- Kramer I,, 2012. Mef2c deletion in osteocytes results in increased bone mass. J. Bone Miner. Res 27, 360– 373. 22161640
- Lambert JC,, 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet 45, 1452– 1458. 24162737 PMC3896259
- Lee-Kirsch MA,, 2015. Type I interferonopathies–an expanding disease spectrum of immunodysregulation. Semin. Immunopathol 37, 349– 357. 25998914
- Li W,, 2018. Microglia have a more extensive and divergent response to interferon-alpha compared with astrocytes. Glia 66, 2058– 2078. 30051922
- Liu CF, Tang WHW, 2019. Epigenetics in cardiac hypertrophy and heart failure. JACC Basic Transl. Sci 4, 976– 993. 31909304 PMC6938823
- Mandrekar S,, 2009. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci 29, 4252– 4262. 19339619 PMC3034143
- Mawuenyega KG,, 2010. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330, 1774. 21148344 PMC3073454
- Mesquita SD,, 2015. The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease. Brain Behav. Immun 49, 280– 292. 26092102
- Minter MR,, 2016. Deletion of the type-1 interferon receptor in APPSWE/PS1DeltaE9 mice preserves cognitive function and alters glial phenotype. Acta Neuropathol. Commun 4, 72. 27400725 PMC4940712
- Moore Z,, 2020. Abrogation of type-I interferon signalling alters the microglial response to Abeta1–42. Sci. Rep 10, 3153. 32081950 PMC7035268
- Mosher KI, Wyss-Coray T, 2014. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594– 604. 24445162 PMC3972294
- Ohsawa K,, 2004. Microglia/macrophage-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity. J. Neurochem 88, 844– 856. 14756805
- Pathan M,, 2015. FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics 15, 2597– 2601. 25921073
- Perea JR,, 2018. The role of microglia in the spread of tau: relevance for Tauopathies. Front. Cell. Neurosci 12, 172. 30042659 PMC6048186
- Pestka S,, 2004. Interferons, interferon-like cytokines, and their receptors. Immunol. Rev 202, 8– 32. 15546383
- Querfurth HW, LaFerla FM, 2010. Alzheimer’s disease. N Engl J Med 362, 329– 344. 20107219
- Rajendran L, Paolicelli RC, 2018. Microglia-mediated synapse loss in Alzheimer’s disease. J. Neurosci 38, 2911– 2919. 29563239 PMC6596066
- Ribeiro LF,, 2014. Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus. Proc. Natl. Acad. Sci. U. S. A 111, E149– E158. 24367106 PMC3890894
- Riedel BC,, 2016. Age, APOE and sex: triad of risk of Alzheimer’s disease. J. Steroid Biochem. Mol. Biol. 160, 134– 147. 26969397 PMC4905558
- Roy ER,, 2020. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J. Clin. Invest. 130, 1912– 1930. 31917687 PMC7108898
- Rusinova I,, 2013. Interferome v2.0: an updated database of annotated interferon-regulated genes. Nucleic Acids Res 41, D1040– D1046. 23203888 PMC3531205
- Sao T,, 2018. MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer’s disease. Psychiatry Clin. Neurosci 72, 160– 167. 29112298
- Sierksma A,, 2020. Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets. Science 370, 61– 66. 33004512
- Smith JA,, 2012. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 87, 10– 20. 22024597 PMC9827422
- Srinivasan K,, 2016. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun 7, 11295. 27097852 PMC4844685
- Tang SS,, 2016. MEF2C rs190982 polymorphism with late-onset Alzheimer’s disease in Han Chinese: a replication study and meta-analyses. Oncotarget 7, 39136– 39142. 27276684 PMC5129919
- Taniguchi T, Takaoka A, 2001. A weak signal for strong responses: interferon-alpha/beta revisited. Nat. Rev. Mol. Cell Biol 2, 378– 386. 11331912
- Tian J,, 2019. Disrupted hippocampal growth hormone secretagogue receptor 1alpha interaction with dopamine receptor D1 plays a role in Alzheimer’s disease. Sci. Transl. Med 11. PMC6776822 31413143
- Torres-Platas SG,, 2014. Morphometric characterization of microglial phenotypes in human cerebral cortex. J. Neuroinflammation 11, 12. 24447857 PMC3906907
- Velazquez-Cruz R,, 2014. Analysis of association of MEF2C, SOST and JAG1 genes with bone mineral density in Mexican-Mestizo postmenopausal women. BMC Musculoskelet. Disord 15, 400. 25430630 PMC4258010
- Venegas C,, 2017. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355– 361. 29293211
- Yegambaram M,, 2015. Role of environmental contaminants in the etiology of Alzheimer’s disease: a review. Curr. Alzheimer Res 12, 116– 146. 25654508 PMC4428475
- Zhao R,, 2017. Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer’s disease. Mol. Neurodegener 12, 47. 28606182 PMC5468952
- Zhou Y,, 2019. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun 10, 1523. 30944313 PMC6447622
- Zuurbier L,, 2014. Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors. Haematologica 99, 94– 102. 23975177 PMC4007923
Cited by
Sorted by citations
Tau Activation of Microglial cGAS–IFN Reduces MEF2C‐mediated Cognitive Resilience
Udeochu, J. C., Amin, S., Huang, Y., Fan, L., Torres, E. R. S., Carling, G. K., Liu, B., McGurran, H., Coronas-Samano, G., Kauwe, G., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01315-6 · Cited by 289 · see citing works
Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease
Kim, B., Wang, S. S., Kim, J. R., & Kim, J. (2026) · BioEssays · doi:10.1002/bies.70186
“In a 5xFAD mouse model of Alzheimer’s disease, decreased microglial MEF2C nuclear translocation contributes to chronic neuroinflammation, which exacerbates neurodegeneration [46].”
Influential
- Authors
- Xue, F., Tian, J., Yu, C., Du, H., & Guo, L.
- Affiliations
- University of Kansas (US)
- Corresponding author
- Du, Heng
- Guo, Lan
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 152
- Pages
- 105272
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7956132
- OpenAlex
- W3126326339
- Cited by
- 32
- References
- 14
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 3 · 2021: 1
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association
- National Institutes of Health
- BrightFocus Foundation
- 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, MEF2C, type I interferon, 5xFAD mice, microglial activation, brain aging, synaptic pruning, microglial phagocytosis, transcription factor nuclear translocation, amyloidosis
- MeSH terms
- Alzheimer Disease, Animals, Humans, Interferon Type I, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Mice, MEF2 Transcription Factors
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
