Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in App NL-G-F mice
Ni Wang, Tammee M Parsons, Yingxue Ren, Yining Pan, Aishe Kurti, Skylar C Starling, Chinenye Muolokwu, Jagdish Singh et al.. Heliyon, 2024-10-18
Topic: Genetics and APOE
Alzheimer's disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The APOE ε2 encoding apolipoprotein E (APOE2) is a protective allele against AD among the three genotypes (APOE ε2, ε3, ε4), while APOE4 is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4. Gene therapy that increases APOE2 levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based APOE2 gene delivery influences Aβ-related pathologies in amyloid model App NL-G-F knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy. Furthermore, in the App NL-G-F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.
Key findings
- APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4.
- We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy.
- On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin.
- Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level.
New to this subject? Start with our plain-English guide: Genetics →
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 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 (Heliyon) |
| 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 | 2024 — 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 | Laboratory or animal study (title names “mice”) — scores zero |
| 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 39506961) |
| 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 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Wang, N., Parsons, T. M., Ren, Y., Pan, Y., Kurti, A., Starling, S. C., et al. (2024). Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in App NL-G-F mice. Heliyon. https://doi.org/10.1016/j.heliyon.2024.e39607
Vancouver
Wang N, Parsons TM, Ren Y, Pan Y, Kurti A, Starling SC, et al. Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in App NL-G-F mice. Heliyon. 2024. doi:10.1016/j.heliyon.2024.e39607. PMID: 39506961.
BibTeX
@article{wang2024-39506961,
author = {Wang, Ni and Parsons, Tammee M and Ren, Yingxue and Pan, Yining and Kurti, Aishe and Starling, Skylar C and Muolokwu, Chinenye and Singh, Jagdish and others},
title = {{Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in App NL-G-F mice}},
journal = {Heliyon},
year = {2024},
doi = {10.1016/j.heliyon.2024.e39607},
pmid = {39506961},
url = {https://doi.org/10.1016/j.heliyon.2024.e39607}
}
Related studies in Genetics
Also tagged “apoe2”
266 studies in the library carry the topic tag “apoe2”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 266 tagged studies.