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Cited by 26Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Hepatic Oxi-Inflammation and Neophobia as Potential Liver–Brain Axis Targets for Alzheimer’s Disease and Aging, with Strong Sensitivity to Sex, Isolation, and Obesity

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Fraile-Ramos, Juan, Garrit, Anna, Reig-Vilallonga, Josep, Giménez-Llort, Lydia·2023·Cells
DOI 10.3390/cells12111517PMC PMC10252497
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Abstract

Research on Alzheimer’s disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease’s pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNF𝛼) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver–brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research.

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Authors
Fraile-Ramos, J., Garrit, A., Reig-Vilallonga, J., & Giménez-Llort, L.
Affiliations
  • Universitat Autònoma de Barcelona (ES)
  • Department of Anatomy, School of Medicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
  • Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-05-30
Volume
12
Issue
11
Pages
1517
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells12111517
PMC
PMC10252497
OpenAlex
W4378904537
Cited by
26
References
0
Citations by year
2026: 3 · 2025: 9 · 2024: 11 · 2023: 3
FWCI
6.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • AGAUR, Generalitat de Catalunya (2017-SGR-1468, UAB-GE-260408, Fet-OPEN-1-2016-2017-737390, 737390, 2021/80/09241941.8)
  • Universitat Autònoma de Barcelona (2017-SGR-1468, UAB-GE-260408, Fet-OPEN-1-2016-2017-737390, 737390, 2021/80/09241941.8)
  • ArrestAD H2020 (2017-SGR-1468, UAB-GE-260408, Fet-OPEN-1-2016-2017-737390, 737390, 2021/80/09241941.8)
  • European Union’s Horizon 2020 research and innovation program (2017-SGR-1468, UAB-GE-260408, Fet-OPEN-1-2016-2017-737390, 737390, 2021/80/09241941.8)
  • Memorial Mercedes Llort Sender (2017-SGR-1468, UAB-GE-260408, Fet-OPEN-1-2016-2017-737390, 737390, 2021/80/09241941.8)
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, liver-brain axis, hepatic oxidative stress, liver inflammation, hepatomegaly, amyloidosis, glutathione peroxidase, glutathione reductase, interleukin-6, TNF-α, 3xTg-AD mice, aging, sex differences, social isolation, hypothalamic-pituitary-adrenal axis, neophobia, obesity, hepatic steatosis
MeSH terms
Aging, Alzheimer Disease, Animals, Brain, Female, Hepatomegaly, Hypothalamo-Hypophyseal System, Inflammation, Male, Mice, Transgenic, Obesity, Pituitary-Adrenal System, Mice

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