Evidence map›Paper›PMID 41409143›Full record

ArticlebioRxiv : the preprint server for biology2025

Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease.

Min Joo Kim, Jessica Blumenfeld, Yaqiao Li, Oscar Yip, Luokang Yao, Stephanie Ancheta, Samuel De Leon, Zoe Platow, Zherui Liang, David Shostak and 6 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Min Joo KimGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Jessica BlumenfeldGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Yaqiao LiGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Oscar YipGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Luokang YaoGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Stephanie AnchetaGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Samuel De LeonGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Zoe PlatowGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Zherui LiangGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
David ShostakGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Kaylie SuanGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Yanxia HaoGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Nicole KoutsodendrisGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Claire EllisGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Jeremy NguyenGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
Yadong HuangGladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.

Funding

Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omicsP01AG073082 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG, MUCKE, LENNART · 2021 to 2025
$23.4M
Neuronal ApoE Drives Selective Neurodegeneration in Alzheimer's DiseaseR01AG071697 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG · 2021 to 2025
$4.1M
Study Susceptibility and Resistance to ApoE4 in Alzheimer's DiseaseRF1AG076647 · NIA · J. DAVID GLADSTONE INSTITUTES · PI HUANG, YADONG · 2022 to 2022
$2.6M
Illumina NovaSeq 6000 Sequencing SystemS10OD028511 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHOW, ERIC D · 2020 to 2020
$583k
NIA NIH HHS P01 AG073082NIA NIH HHS R01 AG071697NIA NIH HHS RF1 AG076647NIH HHS S10 OD028511
6 · The paper itself

Abstract

Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimer's disease (AD). With APOE4 broadly expressed in the brain, its cell-type-specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient for lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes, all promoting lipid pathology. Primary mouse co-culture experiments showed that neuronal APOE4 drives microglial lipid accumulation via contact-dependent mechanisms involving uptake of lipids from neurons and oligodendrocytes. These findings establish neuronal APOE4 as a key driver of lipid accumulation via neuron-oligodendrocyte-microglia interactions, providing mechanistic insight into APOE4-driven lipid pathology in AD.

Identifiers

PMID41409143
PMCPMC12707281

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.