title: Amyloid plaque structure and cell surface interactions of β-amyloid fibrils revealed by electron tomography.
abstract: The deposition of amyloid fibrils as plaques is a key feature of several neurodegenerative diseases including in particular Alzheimer's. This disease is characterized, if not provoked, by amyloid aggregates formed from Aβ peptide that deposit inside the brain or are toxic to neuronal cells. We here used scanning transmission electron microscopy (STEM) to determine the fibril network structure and interactions of Aβ fibrils within a cell culture model of Alzheimer's disease. STEM images taken from the formed Aβ amyloid deposits revealed three main types of fibril network structures, termed amorphous meshwork, fibril bundle and amyloid star. All three were infiltrated by different types of lipid inclusions from small-sized exosome-like structures (50-100 nm diameter) to large-sized extracellular vesicles (up to 300 nm). The fibrils also presented strong interactions with the surrounding cells such that fibril bundles extended into tubular invaginations of the plasma membrane. Amyloid formation in the cell model was previously found to have an intracellular origin and we show here that it functionally destroys the integrity of the intracellular membranes as it leads to lysosomal leakage. These data provide a mechanistic link to explain why intracellular fibril formation is toxic to the cell.
authors.affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
authors.forename: Shen
authors.initials: S
authors.lastname: Han
authors.affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Kollmer
authors.affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Markx
authors.affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Claus
authors.affiliation: Central Facility for Electron Microscopy, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002470:Cell Survival; D002478:Cells, Cultured; D055032:Electron Microscope Tomography; D006801:Humans; D008055:Lipids; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008055:Lipids; D066329:Protein Aggregates