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Peer-reviewedCC BY 4.0Frontiers in Nutrition

Impact of high fat and low vitamin A intervention on cortical transcriptional profiles in APP/PS1 mice and neuronal EEF1AKMT4-ECE2-associated amyloid metabolism

  • Xiuwen Ren1,2
  • Lu Liu1,2
  • Yiran Wang3,4
  • Yu Liu1,2
  • Xixiang Wang1,2
  • Shaobo Zhou5
  • Yunyun Gong6
  • Yueyong Wang1,2
  • Chen Miao1,2
  • Ying Wang7
  • Mengyang Sun1,2
  • Linhong Yuan1,2
7 affiliations
  1. 1School of Public Health, Capital Medical University, Beijing, China
  2. 2Beijing Key Laboratory of Environment and Aging, Beijing, China
  3. 3Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
  4. 4Institute of Reproductive and Child Health, School of Public Health, Peking University, Beijing, China
  5. 5School of Science, Faculty of Engineering and Science, University of Greenwich, Chatham, United Kingdom
  6. 6School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom
  7. 7Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China
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Abstract

Background:: Vitamin A (VA) deficiency and lipid metabolism disorders are associated with the pathogenesis of Alzheimer's disease (AD). However, their effects on cortical gene expression profile and the molecular pathways related to amyloid generation remain insufficiently understood.

Methods: 3-month-old APP/PS1 mice were fed with control, high fat, high fat with normal or low VA containing diets for 8 months. RNA-sequencing technique was applied to measure the cortical gene expression profile. Differentially expressed genes were further validated by real-time quantitative PCR and Western blot analysis. Additionally, SH-SY5Y neuronal cells were used to explore the functional role of the differential expressed molecule EEF1AKMT4-ECE2 (ECE2) in amyloid β (Aβ) metabolism.

Results: Transcriptome analysis identified multiple differentially expressed genes related to diets containing different fat and/or VA, which are mainly involved in amyloid protein metabolism, neuronal differentiation, myelin structure, and metabolic signal transduction. Among them, Ece2 gene was identified as a key nutrient-sensitive gene, showing a significant upregulated expression under high-fat diet intervention. Hes3 and Fam168b were among the differentially expressed genes in the cortical of mice treated with diets contained different dosage of VA, and these genes potentially related to neuronal differentiation and myelin structure. In SH-SY5Y cells, Aβ treatment significantly up-regulated ECE2 protein expression. ECE2 activation rebalanced Aβ species toward Aβ40, yet its efficacy was undermined by high-fat and VA-deficient status, which triggered BACE1 over-expression, ultimately driving intracellular Aβ accumulation and extracellular Aβ40 elevation.

Conclusion: High fat and low VA nutritional status significantly modified the transcriptional profile in the cortex of APP/PS1 mice. ECE2 is a nutrient-sensitive molecule involved in the regulation of cortical Aβ metabolism under high-fat and low-VA conditions.

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Cite

BibTeXRIS
BibTeX
@article{ren2026impact,
  title = {{Impact of high fat and low vitamin A intervention on cortical transcriptional profiles in APP/PS1 mice and neuronal EEF1AKMT4-ECE2-associated amyloid metabolism}},
  author = {Xiuwen Ren and Lu Liu and Yiran Wang and Yu Liu and Xixiang Wang and Shaobo Zhou and Yunyun Gong and Yueyong Wang and Chen Miao and Ying Wang and Mengyang Sun and Linhong Yuan},
  journal = {Frontiers in Nutrition},
  year = {2026},
  month = oct,
  doi = {10.3389/fnut.2026.1923538},
  url = {https://doi.org/10.3389/fnut.2026.1923538},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Impact of high fat and low vitamin A intervention on cortical transcriptional profiles in APP/PS1 mice and neuronal EEF1AKMT4-ECE2-associated amyloid metabolism
AU  - Xiuwen Ren
AU  - Lu Liu
AU  - Yiran Wang
AU  - Yu Liu
AU  - Xixiang Wang
AU  - Shaobo Zhou
AU  - Yunyun Gong
AU  - Yueyong Wang
AU  - Chen Miao
AU  - Ying Wang
AU  - Mengyang Sun
AU  - Linhong Yuan
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Nutrition
DO  - 10.3389/fnut.2026.1923538
UR  - https://doi.org/10.3389/fnut.2026.1923538
AB  - Background:: Vitamin A (VA) deficiency and lipid metabolism disorders are associated with the pathogenesis of Alzheimer's disease (AD). However, their effects on cortical gene expression profile and the molecular pathways related to amyloid generation remain insufficiently understood.  Methods: 3-month-old APP/PS1 mice were fed with control, high fat, high fat with normal or low VA containing diets for 8 months. RNA-sequencing technique was applied to measure the cortical gene expression profile. Differentially expressed genes were further validated by real-time quantitative PCR and Western blot analysis. Additionally, SH-SY5Y neuronal cells were used to explore the functional role of the differential expressed molecule EEF1AKMT4-ECE2 (ECE2) in amyloid β (Aβ) metabolism.  Results: Transcriptome analysis identified multiple differentially expressed genes related to diets containing different fat and/or VA, which are mainly involved in amyloid protein metabolism, neuronal differentiation, myelin structure, and metabolic signal transduction. Among them, Ece2 gene was identified as a key nutrient-sensitive gene, showing a significant upregulated expression under high-fat diet intervention. Hes3 and Fam168b were among the differentially expressed genes in the cortical of mice treated with diets contained different dosage of VA, and these genes potentially related to neuronal differentiation and myelin structure. In SH-SY5Y cells, Aβ treatment significantly up-regulated ECE2 protein expression. ECE2 activation rebalanced Aβ species toward Aβ40, yet its efficacy was undermined by high-fat and VA-deficient status, which triggered BACE1 over-expression, ultimately driving intracellular Aβ accumulation and extracellular Aβ40 elevation.  Conclusion: High fat and low VA nutritional status significantly modified the transcriptional profile in the cortex of APP/PS1 mice. ECE2 is a nutrient-sensitive molecule involved in the regulation of cortical Aβ metabolism under high-fat and low-VA conditions.
SN  - 2296-861X
ER  -