Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo
Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, Ben Aissa M, Thatcher GRJ et al.. The Journal of biological chemistry, 2014-09-12
Topic: Brain proteins, microglia and lab models
Previous data demonstrate that bexarotene (Bex), retinoid X receptor (RXR) agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer disease (AD)-transgenic mice either by increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. However, although the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If the APOE4 loss-of-function is lipidation of apoE4, then induction of ABCA1/ABCG1 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ) are highest in E4FAD hippocampus (HP) > E3FAD-HP > E4FAD cortex (CX) > E3FAD-CX, whereas levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6 months). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6 months) increased ABCA1, apoE4 lipoprotein-association/lipidation, and apoE4/Aβ complex, decreased soluble Aβ, and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG100268. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6 months) and actually increased soluble Aβ levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology, i.e. low levels of apoE4 lipoprotein association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
Key findings
- RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6 months) and actually increased soluble Aβ levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly.
- Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology, i.e. low levels of apoE4 lipoprotein association/lipidation.
Why it matters
In mice carrying the human APOE4 gene, which is the strongest genetic risk factor for Alzheimer's, short-term treatment with retinoid X receptor drugs (bexarotene or LG100268) raised the fat-carrying ("lipidated") form of apoE4 and lowered soluble amyloid in the hippocampus. The same short-term treatment raised soluble amyloid in the cortex, possibly because the drugs enlarged the liver, and a prevention schedule showed no benefit. This is mouse research only. It suggests the APOE4 problem may be too little lipidated apoE4, but it does not show that these drugs help people.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 41/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (OpenAlex, 2026-10-29) |
| 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 | 1 / 5 | 2014 — within 20 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 | 4 / 7 | Cited 93 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.6 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 3 / 6 | Cited 6.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 1 / 4 | Cited 11 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Mary Jo LaDu: h-index 60 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Illinois Chicago: institution h-index 918 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25217640) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Tai, L. M., Koster, K. P., Luo, J., Lee, S. H., Wang, Y. T., Collins, N. C., et al. (2014). Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m114.600833
Vancouver
Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, et al. Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. The Journal of biological chemistry. 2014. doi:10.1074/jbc.m114.600833. PMID: 25217640.
BibTeX
@article{tai2014-25217640,
author = {Tai, L. M. and Koster, K. P. and Luo, J. and Lee, S. H. and Wang, Y. T. and Collins, N. C. and Ben Aissa, M. and Thatcher, G. R. J. and others},
title = {{Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo}},
journal = {The Journal of biological chemistry},
year = {2014},
doi = {10.1074/jbc.m114.600833},
pmid = {25217640},
url = {https://doi.org/10.1074/jbc.m114.600833}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 16.
Later studies that cite this one
7 studies in the alzhub library list this one in their references.
Related studies in Genetics
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.