Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity
Open accessPreprint — published as 10.1016/j.stem.2022.07.005 · Paper page
Abstract
Summary: Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing late- onset Alzheimer’s disease and its expression in microglia is associated with pro- inflammatory states. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral allele APOE3 is currently unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a distinct metabolic program in microglia that is marked by the accumulation of intracellular neutral lipid stores through impaired lipid catabolism. Importantly, this altered lipid-accumulated state shifts microglia away from homeostatic surveillance and renders APOE4 microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia before and after exposure to neuronal conditioned media, we further established that neuronal soluble cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro- inflammatory signals. Pharmacological blockade of lipogenesis in APOE4 microglia is sufficient to diminish intracellular lipid accumulation and restore microglial homeostasis. Remarkably, unlike APOE3 microglia that support neuronal network activity, co-culture of APOE4 microglia with neurons disrupts the coordinated activity of neuronal ensembles. We identified that through decreased uptake of extracellular fatty acids and lipoproteins, APOE4 microglia disrupts the net flux of lipids which results in decreased neuronal activity via the potentiation of the lipid-gated K + channel, GIRK3. These findings suggest that neurological diseases that exhibit abnormal neuronal network-level disturbances may in part be triggered by impairment in lipid homeostasis in non-neuronal cells, underscoring a novel therapeutic route to restore circuit function in the diseased brain. Abstract Figure:
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Altered lipid droplet biology has been linked to both brain aging and neurodegenerative diseases.
“Altered lipid droplet biology has been linked to both brain aging and neurodegenerative diseases10–24.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [13]
Various studies have shown that lipid droplets influence intercellular communication.
“Various studies have shown that lipid droplets influence intercellular communication13,17,61.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [13]
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Research works printed but not linked: 1
- Ralhan, I., Chang, C.L., Lippincott-Schwartz, J., and Ioannou, M.S. (2021). Lipid droplets in the nervous system. J Cell Biol 220 .
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Lee, H., Cho, S., Kim, M.-J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y.-S., Lee, J. Y., Thoudam, T., Woo, S.-H., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113183 · Cited by 93 · see citing works
Cuní-López, C., Root, J. T., Hao, Y., Blomberg, N., Koppes-den Hertog, S. J., Sacks, D., Trujillo, A. E., Ghirlando, R., Kowal, I., Epstein, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-76565-6
- Authors
- Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Bozzelli, P. L., Samaan, G., Murdock, M. H., von Maydell, D., Effenberger, A. H., Cerit, O., Wen, H.-L., Liu, L., Welch, G., Bonner, M., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Broad Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell stem cell
- Publisher
- openRxiv
- Published
- 2022-03-21
- Volume
- 29
- Issue
- 8
- Pages
- 1197-1212.e8
- ISSN
- 1875-9777 (ISSN-L)
- PMC
- PMC9623845
- OpenAlex
- W4289793560
- Cited by
- 311
- References
- 0
- Citations by year
- 2026: 92 · 2025: 102 · 2024: 64 · 2023: 39 · 2022: 13
- FWCI
- 19.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell stem cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute on Aging (R01AG058002, RF1AG062377)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- APOE ε4, APOE3, Alzheimer's disease, microglia, lipid accumulation, neuron-microglia communication, neuronal network activity, pro-inflammatory signaling, lipoprotein uptake, lipid homeostasis, induced pluripotent stem cells, CRISPR gene editing
- MeSH terms
- Alzheimer Disease, Humans, Neurons, Microglia, Apolipoprotein E3, Apolipoprotein E4
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