Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation

Chernyaeva, Larisa ; Ratti, Giorgio ; Teirilä, Laura ; Fudo, Satoshi ; Rankka, Uni ; Pelkonen, Anssi ; Korhonen, Paula ; Leskinen, Katarzyna ; Keskitalo, Salla and Salokas, Kari , et al. (2023) In EMBO Reports 24(7).
Abstract

The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with... (More)

The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apoE, dementia, factor H, inflammation, neurodegeneration
in
EMBO Reports
volume
24
issue
7
publisher
Nature Publishing Group
external identifiers
  • pmid:37155564
  • scopus:85158155858
ISSN
1469-221X
DOI
10.15252/embr.202256467
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
id
8ba1d285-9d5a-4c67-a719-1a453507bcf9
date added to LUP
2023-06-12 22:00:24
date last changed
2024-04-19 23:51:24
@article{8ba1d285-9d5a-4c67-a719-1a453507bcf9,
  abstract     = {{<p>The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.</p>}},
  author       = {{Chernyaeva, Larisa and Ratti, Giorgio and Teirilä, Laura and Fudo, Satoshi and Rankka, Uni and Pelkonen, Anssi and Korhonen, Paula and Leskinen, Katarzyna and Keskitalo, Salla and Salokas, Kari and Gkolfinopoulou, Christina and Crompton, Katrina E. and Javanainen, Matti and Happonen, Lotta and Varjosalo, Markku and Malm, Tarja and Leinonen, Ville and Chroni, Angeliki and Saavalainen, Päivi and Meri, Seppo and Kajander, Tommi and Wollman, Adam J.M. and Nissilä, Eija and Haapasalo, Karita}},
  issn         = {{1469-221X}},
  keywords     = {{apoE; dementia; factor H; inflammation; neurodegeneration}},
  language     = {{eng}},
  number       = {{7}},
  publisher    = {{Nature Publishing Group}},
  series       = {{EMBO Reports}},
  title        = {{Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation}},
  url          = {{http://dx.doi.org/10.15252/embr.202256467}},
  doi          = {{10.15252/embr.202256467}},
  volume       = {{24}},
  year         = {{2023}},
}