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

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.

Ratti, GiorgioHumanitas University (author)
Teirilä, LauraUniversity of Helsinki (author)
Fudo, SatoshiUniversity of Helsinki (author)
Rankka, UniUniversity of Helsinki (author)
Pelkonen, AnssiUniversity of Eastern Finland (author)
Korhonen, PaulaUniversity of Eastern Finland (author)
Leskinen, KatarzynaUniversity of Helsinki (author)
Keskitalo, SallaUniversity of Helsinki (author)
Salokas, KariUniversity of Helsinki (author)
Gkolfinopoulou, Christina (author)
Crompton, Katrina E. (author)
Javanainen, Matti (author)
Happonen, LottaLund University,Lunds universitet,Molekylär patogenes,Forskargrupper vid Lunds universitet,BioMS,Molecular Pathogenesis,Lund University Research Groups(Swepub:lu)immu-loh (author)
Varjosalo, Markku (author)
Malm, Tarja (author)
Leinonen, Ville (author)
Chroni, Angeliki (author)
Saavalainen, Päivi (author)
Meri, Seppo (author)
Kajander, Tommi (author)
Wollman, Adam J.M. (author)
Nissilä, Eija (author)
Haapasalo, Karita (author)
University of HelsinkiHumanitas University (creator_code:org_t)

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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