Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

Victor, Matheus B.; Leary, Noelle; Luna, Xochitl; Meharena, Hiruy S.; Scannail, Aine Ni; Bozzelli, P. Lorenzo; Samaan, George; Murdock, Mitchell H.; von Maydell, Djuna; Effenberger, Audrey H.; Cerit, Oyku; Wen, Hsin-Lan; Liu, Liwang; Welch, Gwyneth; Bonner, Maeve; Tsai, Li-Huei

doi:10.1016/j.stem.2022.07.005

Cited by 328Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

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Victor, Matheus B., Leary, Noelle, Luna, Xochitl, Meharena, Hiruy S., Scannail, Aine Ni, Bozzelli, P. Lorenzo, Samaan, George, Murdock, Mitchell H. +8 more·2022·Cell Stem Cell

DOI 10.1016/j.stem.2022.07.005PMC PMC9623845

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Abstract

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains 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 lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

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APOE4-associated glial LD accumulation modulates neuron function and brain memory.
“and the APOE4-associated glial LD accumulation modulates neuron function and brain memory17–19.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [18]
The Results sections on microglial energetics and lipid-content modulation report increased lipid droplets in APOE4 microglia and show that their conditioned media reduced neuronal bursts; reducing the droplets preserved neuronal activity. The Discussion section on neuronal excitability only proposes a possible detriment to neural computations critical for learning and memory. It does not establish an effect on memory itself. (LLM, conf=0.88)
Experimental — accuracy not yet measured
LDAM have sustained activation, impaired phagocytosis and surveillance, and autophagy dysregulation.
“Among these subsets, LDAM have been given much attention due to their sustained activation, impaired phagocytosis and surveillance, and autophagy dysregulation [26–28].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [27]
The Discussion (page unavailable) describes LDAM as having reduced phagocytosis and increased secretion of pro-inflammatory cytokines, supporting part of the claim. The Results (page unavailable) link impaired homeostatic surveillance to lipid accumulation in APOE4-derived microglia, but do not establish that finding for LDAM. The passages do not support sustained activation or autophagy dysregulation in LDAM. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Recent studies on human induced pluripotent stem cells with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.
“Recent studies on human induced pluripotent stem cells (iPSCs) with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.5”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [6]
The Results section, “Imbalance in the net flux of lipids by APOE4 iMGLs” (page unavailable), reports transcriptional profiling and increased extracellular cholesterol in APOE4 iPSC-derived microglia. The Discussion section, “Cholesterol homeostasis” (page unavailable), reports prior findings of extracellular cholesterol accumulation in APOE4 iPSC-derived astrocytes. The cited paper does not report this finding for oligodendrocytes or describe the claimed metabolomic profiling. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Many LOAD risk-associated genes, such as APOE4, TREM2, and PICALM, have been implicated in regulating microglial immunity and lipid metabolism.
“Many LOAD risk‐associated genes, such as Apolipoprotein E4 (APOE4), 9 , 10 Triggering receptor expressed on myeloid cells 2 (TREM2), 11 and Phosphatidylinositol‑binding clathrin assembly protein (PICALM), 12 have been implicated in regulating microglial immunity and lipid metabolism, 13”
From Aberrant phase separation from a rare ABI3 mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [9]
The Results (page not provided) link APOE4 to altered microglial lipid processing and a pro-inflammatory state, supporting that example. The paper’s reference list mentions a TREM2–APOE pathway, but the passages do not establish the claim for PICALM; the cited paper therefore supports only part of the gene list. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Treating iMGs with triacsin C effectively decreased BODIPY-labelled LDs.
“Treating iMGs with triacsin C (TrC), an inhibitor of long-chain acyl-CoA synthetase that reduces LD formation10,18,19,39,40, effectively decreased BODIPY-labelled LDs (Extended Data Fig. 7e–i).”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [18]

Our findings with PICALM further strengthen the notion of a causal role of LDs in mediating LOAD genetic risk factors.
“Nonetheless, given that the APOE4 allele was recently found to induce LD accumulation in MGs and impair neuronal function18,19, our findings with PICALM further strengthen the notion of a causal role of LDs in mediating LOAD genetic risk factors, providing potential mechanistic targets for AD treatments.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [18]
The APOE4 allele was recently found to induce LD accumulation in MGs and impair neuronal function.
“given that the APOE4 allele was recently found to induce LD accumulation in MGs and impair neuronal function18,19”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [18]
Live cell microscopy showed greater lipid droplet accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG.
“Live cell microscopy of iMG with a fluorescent dye for neutral lipids (LipidSpot) showed greater LD accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG, similar to recent reports in isogenic iMG4 and astrocytes20.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [4]
Human induced pluripotent stem cell-derived microglia with APOE risk variants have more lipid droplets.
“human induced pluripotent stem (iPS) cell-derived microglia (iMG) with APOE risk variants have more lipid droplets (LDs)4.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [4]
Recent work shows deleterious effects of conditioned media on neurons from astrocytes and microglia.
“This approach takes inspiration from recent work showing the deleterious effects of conditioned media on neurons from astrocytes30 and microglia4.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [4]
Lipid accumulation impairs microglial surveillance of neuronal network activity.
“Additionally, lipid accumulation impairs microglial surveillance of neuronal network activity.72”
From Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer’s disease (2024) · cites this paper as [72]

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New insights into innate immunity in Alzheimer’s disease: From APOE protective variants to therapies
Chen, Y., & Holtzman, D. M. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.08.001 · Cited by 19 · see citing works
Deciphering the role of APOE in cerebral amyloid angiopathy: from genetic insights to therapeutic horizons
Hu, H., Wan, S., Hu, Y., Wang, Q., Li, H., & Zhang, N. (2025) · Annals of Medicine · doi:10.1080/07853890.2024.2445194 · Cited by 19 · see citing works
Microglial modulation of neuronal network function and plasticity
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The metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease
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Synergism of ApoE4 and systemic infectious burden is mediated by the APOE ‐ NLRP3 axis in Alzheimer's disease
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APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives
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Neuronal APOE4 Is a Central Orchestrator of Microglial Lipid Accumulation in Alzheimer’s Disease
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Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activityPreprint
Espinoza, A. P. V., Na, N., Campanati, L., Ngo, P., Baldwin, K. K., & Cline, H. T. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.03.668224

Authors: Victor, M. B., Leary, N., Luna, X., Meharena, H. S., Scannail, A. N., 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: Victor, Matheus B.
Meharena, Hiruy S.
Bozzelli, P. Lorenzo
Murdock, Mitchell H.
Effenberger, Audrey H.
Cerit, Oyku
Welch, Gwyneth
Tsai, Li-Huei
Venue: Cell Stem Cell
Publisher: Elsevier BV
Published: 2022-08
Volume: 29
Issue: 8
Pages: 1197-1212.e8
ISSN: 1875-9777 (ISSN-L)
1934-5909
DOI: 10.1016/j.stem.2022.07.005
PMC: PMC9623845
OpenAlex: W4289793560
Cited by: 316
References: 137
Citations by year: 2026: 81 · 2025: 105 · 2024: 73 · 2023: 43 · 2022: 13
FWCI: 21.50
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
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 (AG058002)
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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Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

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