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Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation
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- Chernyaeva, Larisa (author)
- University of Helsinki
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- Ratti, Giorgio (author)
- Humanitas University
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- Teirilä, Laura (author)
- University of Helsinki
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- Fudo, Satoshi (author)
- University of Helsinki
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- Rankka, Uni (author)
- University of Helsinki
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- Pelkonen, Anssi (author)
- University of Eastern Finland
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- Korhonen, Paula (author)
- University of Eastern Finland
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- Leskinen, Katarzyna (author)
- University of Helsinki
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- Keskitalo, Salla (author)
- University of Helsinki
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- Salokas, Kari (author)
- University of Helsinki
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Gkolfinopoulou, Christina (author)
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Crompton, Katrina E. (author)
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Javanainen, Matti (author)
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- Happonen, Lotta (author)
- Lund University,Lunds universitet,Molekylär patogenes,Forskargrupper vid Lunds universitet,BioMS,Molecular Pathogenesis,Lund University Research Groups
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Varjosalo, Markku (author)
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Malm, Tarja (author)
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Leinonen, Ville (author)
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Chroni, Angeliki (author)
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Saavalainen, Päivi (author)
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Meri, Seppo (author)
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Kajander, Tommi (author)
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Wollman, Adam J.M. (author)
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Nissilä, Eija (author)
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Haapasalo, Karita (author)
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(creator_code:org_t)
- 2023
- English.
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In: EMBO Reports. - 1469-221X. ; 24:7
- Related links:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- apoE
- dementia
- factor H
- inflammation
- neurodegeneration
Publication and Content Type
- art (subject category)
- ref (subject category)
To the university's database
- By the author/editor
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Chernyaeva, Lari ...
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Ratti, Giorgio
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Teirilä, Laura
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Fudo, Satoshi
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Rankka, Uni
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Pelkonen, Anssi
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show more...
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Korhonen, Paula
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Leskinen, Katarz ...
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Keskitalo, Salla
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Salokas, Kari
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Gkolfinopoulou, ...
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Crompton, Katrin ...
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Javanainen, Matt ...
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Happonen, Lotta
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Varjosalo, Markk ...
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Malm, Tarja
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Leinonen, Ville
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Chroni, Angeliki
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Saavalainen, Päi ...
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Meri, Seppo
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Kajander, Tommi
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Wollman, Adam J. ...
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Nissilä, Eija
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Haapasalo, Karit ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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EMBO Reports
- By the university
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Lund University