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PreprintCited by 2Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAutophagy in Disease and Therapy

MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages

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Goate, Alison, Podlesny-Drabiniok, Anna, Kim, Jeanne, Bezemer, Lotte, Patel, Tulsi, Cheng, Haoxiang, Sewell, Michael, Montecillo, Mia +4 more·2026·Research Square
DOI 10.21203/rs.3.rs-9164252/v1PMC PMC13142631
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Abstract

Risk alleles for late-onset Alzheimer’s disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature—spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)—emerges across neurodegenerative and metabolic diseases characterized by lipid overload, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C—a candidate AD risk gene—is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked candidate causal variants in AD risk loci to MEF2C-regulated cis-regulatory elements that target candidate AD risk genes at these loci. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a potential biological mechanism to modulate AD-relevant pathology.

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  • Disease-associated, lipid-associated, and potentially suppressive microglial programs may emerge when key myeloid transcription factors are shifted quantitatively rather than completely removed.

    “Disease-associated, lipid-associated, and potentially suppressive microglial programs may emerge when key myeloid transcription factors are shifted quantitatively rather than completely removed.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [25]

    The Results section on partial MEF2C reduction in iPSC-derived microglia (page unavailable) reports increased DLAM markers without complete removal of MEF2C. The Discussion also describes MEF2C reduction as polarizing microglia toward disease- and lipid-associated states. Our copy does not establish that partial reduction induces a suppressive microglial program; suppression of homeostatic or proliferative genes is not the same claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Podlesny-Drabiniok et al. linked MEF2C-regulated regulatory elements to candidate Alzheimer's disease risk genes and showed that, in a human triculture model containing Alzheimer's disease neurons and astrocytes, MEF2C-deficient microglia were associated with an increased DLAM population and a reduced Aβ42/40 ratio.

    “Importantly, the authors linked MEF2C-regulated regulatory elements to candidate Alzheimer’s disease risk genes and showed that, in a human triculture model containing Alzheimer’s disease neurons and astrocytes, MEF2C-deficient microglia were associated with an increased DLAM population and a reduced Aβ42/40 ratio [25].”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [25]

  • Protective Alzheimer's-associated microglial responses may require precise state tuning rather than broad activation or suppression.

    “These observations strengthen the view that protective Alzheimer ’s-associated microglial responses may require precise state tuning rather than broad activation or suppression.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [25]

  • In human iPSC-derived microglia and macrophage models, total or partial MEF2C reduction was sufficient to induce a DLAM-like state characterized by lysosomal, phagocytic, lipid-handling, and cholesterol-efflux pathways.

    “In human iPSC-derived microglia and macrophage models, total or partial MEF2C reduction was sufficient to induce a DLAM-like state characterized by lysosomal, phagocytic, lipid-handling, and cholesterol-efflux pathways.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [25]

  • Recent work on MEF2C supports the idea that Alzheimer's-associated microglial states are governed by transcription-factor dosage rather than by a simple activated-versus-resting switch.

    “Recent work on MEF2C further supports the idea that Alzheimer ’s-associated microglial states are governed by transcription-factor dosage rather than by a simple activated-versus-resting switch.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [25]

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Authors
Goate, A., Podlesny-Drabiniok, A., Kim, J., Bezemer, L., Patel, T., Cheng, H., Sewell, M., Montecillo, M., Church, N., Walley, A., Garretti, F., & Marcora, E.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
ORCID
Venue
Research Square
Publisher
Springer Science and Business Media LLC
Published
2026-04-28
DOI
10.21203/rs.3.rs-9164252/v1
PMC
PMC13142631
OpenAlex
W7156664514
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0
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Type
posted content
Language
en
Open access
Licence
Locations
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • National Institutes of Health (1s10od026880-01, 1s10od030463-01, UL1TR004419)
  • National Institute on Aging (U01AG058635, RF1AG054011)
  • National Heart, Lung, and Blood Institute (R01HL168174)
  • National Institute of Allergy and Infectious Diseases (T32AI078892)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
MEF2C, Alzheimer's disease, macrophages, microglia, lipid-associated macrophages, lysosomal clearance, cholesterol efflux, lipid metabolism, cis-regulatory elements, chromatin accessibility, epigenetic regulation, amyloid-beta, Aβ42/Aβ40 ratio

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