Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice
Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE.. The Journal of biological chemistry, 2015-07-10
Topic: Brain proteins, microglia and lab models
Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid β (Aβ), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aβ. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Skerrett, R., Pellegrino, M. P., Casali, B. T., Taraboanta, L., & Landreth, G. E. (2015). Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m115.652008
Vancouver
Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. The Journal of biological chemistry. 2015. doi:10.1074/jbc.m115.652008. PMID: 26163517.
BibTeX
@article{skerrett2015-26163517,
author = {Skerrett, R. and Pellegrino, M. P. and Casali, B. T. and Taraboanta, L. and Landreth, G. E.},
title = {{Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice}},
journal = {The Journal of biological chemistry},
year = {2015},
doi = {10.1074/jbc.m115.652008},
pmid = {26163517},
url = {https://doi.org/10.1074/jbc.m115.652008}
}
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Key findings
- Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE).
- Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model.
- We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus.
- The decrease in plaques was associated with increased colocalization between microglia and plaques.
- These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.
Why it matters
In a mouse model of Alzheimer disease, combining two drugs that target LXR and PPARγ reduced amyloid beta levels and improved behavior. These are early animal findings, and it is not yet known whether the same combination would be safe or effective in people.
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Study details
- Evidence strengthLow
How this study scored 44/100
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.
| 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 | 2015 — 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 | 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 | 4 / 7 | Cited 88 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.8 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 3 / 6 | Cited 6.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 2 / 4 | Cited 19 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Gary E. Landreth: h-index 101 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Case Western Reserve University: institution h-index 1,159 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26163517) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 44 / 100 | — |
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