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Cited by 10Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsOral microbiology and periodontitis research

Chronic Lipopolysaccharide Exposure Causes AD ‐Like Pathology in Male Mice With Intact Blood–Brain Barrier

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Eid, Fady, Boushehri, Mohammad, Boucher, Chloé, Rajkanth, Nischwethaa, Sa, Ana Flor, Alhoutan, Thamir, Vavetsi, Konstantina, Dibart, Serge +1 more·2025·The FASEB Journal
DOI 10.1096/fj.202403117rr
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Abstract

Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late‐onset Alzheimer's disease (AD). Gram‐negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation‐inducing molecule in Gram‐negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra‐acylated and penta‐acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa‐acylated lipid A. Whether P. gingivalis ‐LPS and E. coli ‐LPS play a similar role in the progression of late‐onset AD is unknown. Using adult, wild‐type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28‐day, subcutaneous infusion of P. gingivalis ‐LPS or E. coli ‐LPS can lead to neuroinflammation and AD‐like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood–brain barrier is intact, both P. gingivalis ‐LPS and E. coli ‐LPS cause neuroinflammation through Toll‐like receptor 4 (TLR4) and Toll‐like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli ‐LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis ‐LPS release (occurring in chronic periodontitis) or E. coli ‐LPS release (occurring in IBD) could harm the brain before the blood–brain barrier is disrupted; continuous local P. gingivalis ‐LPS release might do harm to the brain before exhibiting adverse effects systemically.

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  • LPS from Escherichia coli promotes Aβ aggregation, while systemic inflammation enhances tau hyperphosphorylation through kinase activation.

    “LPS from Escherichia coli promotes Aβ aggregation, while systemic inflammation enhances tau hyperphosphorylation through kinase activation [129].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [129]

    The Results report increased APP and phosphorylated tau in E. coli-LPS-treated mice, and the Discussion reports systemic inflammation. They do not show that E. coli-LPS promotes Aβ aggregation; the kinase-and-phosphatase explanation for tau hyperphosphorylation is reported from another study, not established as the mechanism in these mice. Page numbers were not available in our copy. (LLM, conf=0.86)

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Cited by

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Authors
Eid, F., Boushehri, M., Boucher, C., Rajkanth, N., Sa, A. F., Alhoutan, T., Vavetsi, K., Dibart, S., & Ma, Y.
Affiliations
Boston University (US)
Corresponding author
Ma, Yun
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2025-05-03
Volume
39
Issue
9
Pages
e70601-e70601
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.202403117rr
OpenAlex
W4410058425
Cited by
10
References
12
Citations by year
2026: 6 · 2025: 4
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (1s10od024993-01)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
lipopolysaccharide, Alzheimer's disease, Porphyromonas gingivalis, Escherichia coli, lipid A, neuroinflammation, blood-brain barrier, TLR4, TLR2, microglia, periodontitis, inflammatory bowel disease, cognitive decline, chronic inflammation, Gram-negative bacteria
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Escherichia coli, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Porphyromonas gingivalis, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice

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