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Cited by 330Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model

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Kim, Do-Geun, Krenz, Antje, Toussaint, Leon E., Maurer, Kirk J., Robinson, Sudie-Ann, Yan, Angela, Torres, Luisa, Bynoe, Margaret S.·2016·Journal of Neuroinflammation
DOI 10.1186/s12974-015-0467-5PMC PMC4700622
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Abstract

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world's population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. METHODS: WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. RESULTS: During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. CONCLUSIONS: Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition.

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Authors
Kim, D.-G., Krenz, A., Toussaint, L. E., Maurer, K. J., Robinson, S.-A., Yan, A., Torres, L., & Bynoe, M. S.
Affiliations
  • Cornell University (US)
  • Dartmouth College (US)
Corresponding author
Bynoe, Margaret S.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2016-01-05
Volume
13
Issue
1
Pages
1-1
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-015-0467-5
PMC
PMC4700622
OpenAlex
W2223511468
Cited by
330
References
10
Citations by year
2026: 10 · 2025: 29 · 2024: 43 · 2023: 32 · 2022: 35 · 2021: 59 · 2020: 43 · 2019: 20 · 2018: 22 · 2017: 25 · 2016: 11 · 2013: 1
FWCI
17.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01 NS063011, R01 NS078018)
  • Kwanjeong Educational Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
non-alcoholic fatty liver disease, Alzheimer's disease, high-fat diet, APP transgenic mice, liver inflammation, neuroinflammation, microglial activation, Toll-like receptors, LRP1, amyloid-beta clearance, neuronal apoptosis, amyloid plaques, neurodegeneration
MeSH terms
Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Calcium-Binding Proteins, Disease Models, Animal, Fats, Gene Expression Regulation, Humans, Mice, Transgenic, Microfilament Proteins, Mutation, Nerve Tissue Proteins, Receptors, LDL, Cytokines, Amyloid beta-Protein Precursor, Neutrophil Infiltration, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Toll-Like Receptors, Mice, Plaque, Amyloid, Diet, High-Fat, Non-alcoholic Fatty Liver Disease

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