ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition
Erika Di Biase, Kyle J Connolly, Ingrid Crumpton, Oliver Cooper, Penelope J Hallett, Ole Isacson. Scientific reports, 2025-04-29
Topic: Genetics and APOE
Apolipoprotein E (ApoE) variants are central to Alzheimer's disease (AD), Lewy body dementia (LBD) and Niemann-Pick disease type C (NPC). The ApoE4 variant elevates AD risk by 3-15-fold. ApoE's normal function in lipid transport is known. The question remains how different ApoE isoforms cause cellular pathogenesis. We determined the effects of ApoE isoforms on lipid accumulation induced by inhibiting the endo-lysosomal cholesterol transporter NPC1. In human fibroblasts and astrocytes, NPC1 inhibition caused a 4-fold cholesterol accumulation and mis-localization with altered cholesterol sensing and increased synthesis of cholesterol and triglycerides. Total APP, APP C-terminal fragments (CTF) and BACE1 levels increased 3-fold. Remarkably, the intracellular neutral lipids co-localized with APP and APP C-terminal fragments. ApoE2 and ApoE3, but not ApoE4, reduced intracellular cholesterol levels by 67% and 62%, respectively, normalized APP, BACE, CTF, and improved cell survival. ApoE4 combined with a synthetic lipopeptide, which increased the proportion of large lipidated ApoE4 particles, corrected these abnormalities. This highlights ApoE in lipid pathogenesis and targeting ApoE4 lipidation to restore ApoE4 function.
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APA 7th
Di Biase, E., Connolly, K. J., Crumpton, I., Cooper, O., Hallett, P. J., & Isacson, O. (2025). ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition. Scientific reports. https://doi.org/10.1038/s41598-025-96531-4
Vancouver
Di Biase E, Connolly KJ, Crumpton I, Cooper O, Hallett PJ, Isacson O. ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition. Scientific reports. 2025. doi:10.1038/s41598-025-96531-4. PMID: 40301465.
BibTeX
@article{dibiase2025-40301465,
author = {Di Biase, Erika and Connolly, Kyle J and Crumpton, Ingrid and Cooper, Oliver and Hallett, Penelope J and Isacson, Ole},
title = {{ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition}},
journal = {Scientific reports},
year = {2025},
doi = {10.1038/s41598-025-96531-4},
pmid = {40301465},
url = {https://doi.org/10.1038/s41598-025-96531-4}
}
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Key findings
- Total APP, APP C-terminal fragments (CTF) and BACE1 levels increased 3-fold.
- Remarkably, the intracellular neutral lipids co-localized with APP and APP C-terminal fragments.
- ApoE2 and ApoE3, but not ApoE4, reduced intracellular cholesterol levels by 67% and 62%, respectively, normalized APP, BACE, CTF, and improved cell survival.
- ApoE4 combined with a synthetic lipopeptide, which increased the proportion of large lipidated ApoE4 particles, corrected these abnormalities.
- This highlights ApoE in lipid pathogenesis and targeting ApoE4 lipidation to restore ApoE4 function.
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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 (Scientific reports) |
| 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 40301465) |
| 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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