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Apolipoprotein E3 and E4 isoforms exhibit differing effects in countering endotoxins

Puthia, Manoj LU ; Marzinek, Jan K. ; Vesela, Katerina ; Larsson, Axel ; Schmidtchen, Artur LU ; Bond, Peter J. and Petrlova, Jitka LU (2025) In Journal of Biological Chemistry 301(3).
Abstract

Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The... (More)

Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The presence of LPS induced the aggregation of APOE isoforms, a phenomenon confirmed through specific amyloid staining, as well as fluorescence and electron microscopy. The scavenging effects of APOE3/4 isoforms were studied through both in vitro and in vivo experiments. In summary, our study established that APOE isoforms exhibit binding to LPS, with a more pronounced affinity and complex formation observed for APOE4 compared with APOE3. Furthermore, our data suggest that APOE isoforms neutralize LPS through aggregation, leading to a reduction of local inflammation in experimental animal models. In addition, both isoforms demonstrated inhibitory effects on the growth of P. aeruginosa and E. coli. These findings provide new insights into the multifunctionality of APOE in the human body, particularly its role in innate immunity during bacterial infections.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antimicrobial peptides, apolipoprotein E isoforms, endotoxin, host defense, protein aggregation
in
Journal of Biological Chemistry
volume
301
issue
3
article number
108236
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:39880097
  • scopus:85217910057
ISSN
0021-9258
DOI
10.1016/j.jbc.2025.108236
language
English
LU publication?
yes
id
7e1e8455-1fb9-4af3-9178-cd43e50187f6
date added to LUP
2025-06-19 11:49:31
date last changed
2025-07-03 14:05:06
@article{7e1e8455-1fb9-4af3-9178-cd43e50187f6,
  abstract     = {{<p>Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The presence of LPS induced the aggregation of APOE isoforms, a phenomenon confirmed through specific amyloid staining, as well as fluorescence and electron microscopy. The scavenging effects of APOE3/4 isoforms were studied through both in vitro and in vivo experiments. In summary, our study established that APOE isoforms exhibit binding to LPS, with a more pronounced affinity and complex formation observed for APOE4 compared with APOE3. Furthermore, our data suggest that APOE isoforms neutralize LPS through aggregation, leading to a reduction of local inflammation in experimental animal models. In addition, both isoforms demonstrated inhibitory effects on the growth of P. aeruginosa and E. coli. These findings provide new insights into the multifunctionality of APOE in the human body, particularly its role in innate immunity during bacterial infections.</p>}},
  author       = {{Puthia, Manoj and Marzinek, Jan K. and Vesela, Katerina and Larsson, Axel and Schmidtchen, Artur and Bond, Peter J. and Petrlova, Jitka}},
  issn         = {{0021-9258}},
  keywords     = {{antimicrobial peptides; apolipoprotein E isoforms; endotoxin; host defense; protein aggregation}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Apolipoprotein E3 and E4 isoforms exhibit differing effects in countering endotoxins}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2025.108236}},
  doi          = {{10.1016/j.jbc.2025.108236}},
  volume       = {{301}},
  year         = {{2025}},
}