Cited by 77Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Liu, Pai, Wang, Zhi-Hao, Kang, Seong Su, Liu, Xia, Xia, Yiyuan, Chan, Chi-Bun, Ye, Keqiang·2022·Molecular Psychiatry

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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  • Midlife central obesity increases the risk of dementia as high as 3.6 times, possibly by activating systemic inflammation, thus worsening astrogliosis, microgliosis, neuroinflammation and amyloid-β pathology.

    “Epidemiological study has found that midlife central obesity increases risk of dementia as high as 3.6 times,372 possibly by activating systemic inflammation, thus worsening astrogliosis, microgliosis, neuroinflammation and Aβ pathology.373,374”

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Authors
Liu, P., Wang, Z.-H., Kang, S. S., Liu, X., Xia, Y., Chan, C.-B., & Ye, K.
Affiliations
  • Emory University (US)
  • University of Hong Kong (HK)
Corresponding author
Ye, Keqiang
Venue
Molecular Psychiatry
Published
2022-05-11
Volume
27
Issue
8
Pages
3396-3409
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
OpenAlex
W4280498767
Cited by
77
References
42
Citations by year
2026: 16 · 2025: 26 · 2024: 26 · 2023: 6 · 2022: 3
FWCI
9.43
Type
journal article
Language
en
Open access
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Emory University
  • National Natural Science Foundation of China (82101479)
  • National Institutes of Health (UL1TR002378)
  • School of Medicine, Emory University (UL1-TR002378)
  • National Institute on Aging (R01AG065177)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, type 3 diabetes, high-fat diet, insulin resistance, C/EBPβ, AEP, inflammation, lipopolysaccharide, amyloid-beta deposition, tau hyperphosphorylation, cognitive impairment, aspirin, obesity, neuronal signaling
MeSH terms
Alzheimer Disease, Animals, Brain, Diabetes Mellitus, Disease Models, Animal, Inflammation, Insulin Resistance, Mice, Transgenic, CCAAT-Enhancer-Binding Protein-beta, Mice, Diet, High-Fat

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