High-fat diet-induced diabetes couples to Alzheimer’s disease through inflammation-activated C/EBPβ/AEP pathway
Open accessAbstract
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”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [373]
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“155,156 In PD models, AEP cleaves α-synuclein into toxic fragments, facilitating Lewy body formation and neuronal damage.”
- 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
- PMC
- PMC10032575
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- 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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