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High-fat diet-induced diabetes couples to Alzheimer’s disease through inflammation-activated C/EBPβ/AEP pathway

Molecular Psychiatry volume 27, pages 3396–3409 (2022)Cite this article

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Abstract

Diabetes is a risk factor for Alzheimer’s disease (AD), which is also called type 3 diabetes with insulin reduction and insulin resistance in AD patient brains. However, the molecular mechanism coupling diabetes to AD onset remains incompletely understood. Here we show that inflammation, associated with obesity and diabetes elicited by high-fat diet (HFD), activates neuronal C/EBPβ/AEP signaling that drives AD pathologies and cognitive disorders. HFD stimulates diabetes and insulin resistance in neuronal Thy1-C/EBPβ transgenic (Tg) mice, accompanied with prominent mouse Aβ accumulation and hyperphosphorylated Tau aggregation in the brain, triggering cognitive deficits. These effects are profoundly diminished when AEP is deleted from C/EBPβ Tg mice. Chronic treatment with inflammatory lipopolysaccharide (LPS) facilitates AD pathologies and cognitive disorders in C/EBPβ Tg but not in wild-type mice, and these deleterious effects were substantially alleviated in C/EBPβ Tg/AEP −/− mice. Remarkably, the anti-inflammatory drug aspirin strongly attenuates HFD-induced diabetes and AD pathologies in neuronal C/EBPβ Tg mice. Therefore, our findings demonstrate that inflammation-activated neuronal C/EBPβ/AEP signaling couples diabetes to AD.

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Fig. 1: High-Fat Diet (HFD) induces diabetes in Thy1-C/EBPβ transgenic mice.
Fig. 2: High-Fat Diet (HFD) impairs insulin signaling and diminishes AMPK/ACC pathways in Thy1-C/EBPβ transgenic mice.
Fig. 3: Knockout of AEP from Thy1-C/EBPβ transgenic mice alleviates HFD-induced neuro-inflammation and AD pathologies.
Fig. 4: Deletion of AEP from Thy1-C/EBPβ transgenic mice ameliorates HFD-triggered synaptic degeneration and cognitive dysfunctions.
Fig. 5: LPS triggers APP and Tau cleavage and neuro-inflammation in Thy1-C/EBPβ transgenic mice via activating C/EBPβ/AEP signaling.
Fig. 6: LPS induces AD pathologies and cognitive deficits in Thy1-C/EBPβ transgenic mice.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

The authors are thankful for Dr Randy Hall in the Department of Pharmacology and Chemical Biology at Emory University for critical proofreading the manuscript and providing a lot of valuable advice. This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. This study was supported in part by the Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology and Chemical Biology, Emory University School of Medicine, and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.

Funding

This work was supported by grants from NIH grant (RO1, AG065177) to KY. and National Natural Science Foundation (NSFC) of China (No. 82101479) to ZHW.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Pai Liu, Zhi-Hao Wang, Seong Su Kang, Xia Liu, Yiyuan Xia & Keqiang Ye

  2. Neuroscience Program, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Pai Liu

  3. Department of Neurology, Renmin Hospital, Wuhan University School of Medicine, Wuhan, Hubei Province, China

    Zhi-Hao Wang

  4. School of Biological Sciences, The University of Hong Kong, 6N01 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong, China

    Chi-Bun Chan

  5. Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China

    Keqiang Ye

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Contributions

KY conceived the project, designed the experiments, analyzed the data, and wrote the paper. PL, ZHW, SSK, YX, designed and performed most of the experiments. XL assisted with animal experiments. CBC designed experiments and critically read the paper.

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Correspondence to Keqiang Ye.

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Liu, P., Wang, ZH., Kang, S.S. et al. High-fat diet-induced diabetes couples to Alzheimer’s disease through inflammation-activated C/EBPβ/AEP pathway. Mol Psychiatry 27, 3396–3409 (2022). https://doi.org/10.1038/s41380-022-01600-z

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