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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\u2010specific binding of apoE to FH alters A\u03b21\u201042\u2010mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of A\u03b21\u201042 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement\u2010resistant oligomers with apoE\/A\u03b21\u201042 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 A\u03b21\u201042 oligomerization and toxicity, and colocalize with complement activator C1q deposited on A\u03b2 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.\n                  <\/jats:p>","DOI":"10.15252\/embr.202256467","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T14:19:27Z","timestamp":1683555567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Reduced binding of apoE4 to complement factor H\u00a0promotes amyloid\u2010\u03b2 oligomerization and neuroinflammation"],"prefix":"10.1038","volume":"24","author":[{"given":"Larisa","family":"Chernyaeva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9938-2752","authenticated-orcid":false,"given":"Giorgio","family":"Ratti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Teiril\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9925-5131","authenticated-orcid":false,"given":"Satoshi","family":"Fudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0061-627X","authenticated-orcid":false,"given":"Uni","family":"Rankka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anssi","family":"Pelkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-1474","authenticated-orcid":false,"given":"Paula","family":"Korhonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Leskinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-1975","authenticated-orcid":false,"given":"Salla","family":"Keskitalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4471-6698","authenticated-orcid":false,"given":"Kari","family":"Salokas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Gkolfinopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina 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