APOE genotype-dependent differences in human astrocytic energy metabolism
Vanessa Budny, Chantal Bodenmann, Kathrin J Zürcher, Maik Krüger, Sherida M de Leeuw, Rebecca Z Weber, Ruslan Rust, Luca Ravotto et al.. Frontiers in cellular neuroscience, 2025-09-01
Topic: Genetics and APOE
ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in APOE4 iAstrocytes. In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in APOE4 iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that APOE does not affect lactate dynamics. In agreement with the increased glycolytic activity, APOE4 iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test. This was accompanied by elevated proton leak in APOE4 iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected. Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in APOE4 compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis. In general, APOE2 and APOE-KO iAstrocytes showed a very similar phenotype in all functional assays and differences between APOE2/APOE-KO and APOE4 were stronger than between APOE3 and APOE4. Our study provides evidence for APOE genotype-dependent effects on astrocyte energy metabolism and highlights alterations in the bioenergetic processes of the brain as important pathomechanisms in AD.
Key findings
- ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in APOE4 iAstrocytes.
- In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in APOE4 iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that APOE does not affect lactate dynamics.
- In agreement with the increased glycolytic activity, APOE4 iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test.
- This was accompanied by elevated proton leak in APOE4 iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected.
- Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in APOE4 compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Frontiers in cellular neuroscience) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40958776) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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APA 7th
Budny, V., Bodenmann, C., Zürcher, K. J., Krüger, M., de Leeuw, S. M., Weber, R. Z., et al. (2025). APOE genotype-dependent differences in human astrocytic energy metabolism. Frontiers in cellular neuroscience. https://doi.org/10.3389/fncel.2025.1603657
Vancouver
Budny V, Bodenmann C, Zürcher KJ, Krüger M, de Leeuw SM, Weber RZ, et al. APOE genotype-dependent differences in human astrocytic energy metabolism. Frontiers in cellular neuroscience. 2025. doi:10.3389/fncel.2025.1603657. PMID: 40958776.
BibTeX
@article{budny2025-40958776,
author = {Budny, Vanessa and Bodenmann, Chantal and Zürcher, Kathrin J and Krüger, Maik and de Leeuw, Sherida M and Weber, Rebecca Z and Rust, Ruslan and Ravotto, Luca and others},
title = {{APOE genotype-dependent differences in human astrocytic energy metabolism}},
journal = {Frontiers in cellular neuroscience},
year = {2025},
doi = {10.3389/fncel.2025.1603657},
pmid = {40958776},
url = {https://doi.org/10.3389/fncel.2025.1603657}
}