title: Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner.
abstract: Progressive accumulation of PrP(Sc), a hallmark of prion diseases, occurs when conversion of PrP(C) into PrP(Sc) is faster than PrP(Sc) clearance. Engulfment of apoptotic bodies by phagocytes is mediated by Mfge8 (milk fat globule epidermal growth factor 8). In this study, we show that brain Mfge8 is primarily produced by astrocytes. Mfge8 ablation induced accelerated prion disease and reduced clearance of cerebellar apoptotic bodies in vivo, as well as excessive PrP(Sc) accumulation and increased prion titers in prion-infected C57BL/6 × 129Sv mice and organotypic cerebellar slices derived therefrom. These phenotypes correlated with the presence of 129Sv genomic markers in hybrid mice and were not observed in inbred C57BL/6 Mfge8(-/-) mice, suggesting the existence of additional strain-specific genetic modifiers. Because Mfge8 receptors are expressed by microglia and depletion of microglia increases PrP(Sc) accumulation in organotypic cerebellar slices, we conclude that engulfment of apoptotic bodies by microglia may be an important pathway of prion clearance controlled by astrocyte-borne Mfge8.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Kranich
authors.forename: Nike Julia
authors.initials: NJ
authors.lastname: Krautler
authors.forename: Jeppe
authors.initials: J
authors.lastname: Falsig
authors.forename: Boris
authors.initials: B
authors.lastname: Ballmer
authors.forename: Shulei
authors.initials: S
authors.lastname: Li
authors.forename: Gregor
authors.initials: G
authors.lastname: Hutter
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: Rita
authors.initials: R
authors.lastname: Moos
authors.forename: Christian
authors.initials: C
authors.lastname: Julius
authors.forename: Gino
authors.initials: G
authors.lastname: Miele
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis*; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008894:Milk Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013045:Species Specificity
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D018620:PrPSc Proteins