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Lipopolysaccharide alters the blood–brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) brains are characterized by accumulation of amyloid beta protein (Abeta) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Abeta accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Abeta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Abeta, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Abeta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Abeta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Abeta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Abeta. Thus, inflammation potentially increases brain levels of Abeta by three mechanisms: increased influx, decreased efflux, and increased neuronal production.
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“High plasma levels of endotoxin can increase permeability of the blood-brain barrier, allowing toxic plasma components, including amyloid β and α-synuclein into the brain [49–51].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [51]
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Metadata
- Authors
- Jaeger, L. B., Dohgu, S., Sultana, R., Lynch, J. L., Owen, J. B., Erickson, M. A., Shah, G. N., Price, T. O., Fleegal-Demotta, M. A., Butterfiled, D. A., & Banks, W. A.
- Affiliations
- St. Louis VA Medical Center (US)
- University of Kentucky (US)
- Corresponding author
- Banks, William A.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 23
- Issue
- 4
- Pages
- 507-517
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2783557
- OpenAlex
- W2156015902
- Cited by
- 281
- References
- 64
- Citations by year
- 2026: 20 · 2025: 17 · 2024: 23 · 2023: 13 · 2022: 16 · 2021: 21 · 2020: 19 · 2019: 14 · 2018: 11 · 2017: 22 · 2016: 17 · 2015: 9 · 2014: 21 · 2013: 17 · 2012: 13
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-11-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG029839)
- National Institute of Neurological Disorders and Stroke (R01NS050547, R01NS051334)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta, blood-brain barrier, lipopolysaccharide, neuroinflammation, indomethacin, LRP1, RAGE, triolein, interleukins, MCP-1
- MeSH terms
- Receptor for Advanced Glycation End Products, Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Dose-Response Relationship, Drug, Indomethacin, Inflammation, Lipopolysaccharides, Male, Receptors, Immunologic, Receptors, LDL, Triolein, Blotting, Western, Cytokines, Amyloid beta-Peptides, Cyclooxygenase Inhibitors, Oxidative Stress, Disease Progression, Protein Transport, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice
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