title: Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons.
abstract: Despite the clear physical association between activated astrocytes and amyloid-β (Aβ) plaques, the importance of astrocytes and their therapeutic potential in Alzheimer's disease remain elusive. Soluble Aβ aggregates, such as protofibrils, have been suggested to be responsible for the widespread neuronal cell death in Alzheimer's disease, but the mechanisms behind this remain unclear. Moreover, ineffective degradation is of great interest when it comes to the development and progression of neurodegeneration. Based on our previous results that astrocytes are extremely slow in degrading phagocytosed material, we hypothesized that astrocytes may be an important player in these processes. Hence, the aim of this study was to clarify the role of astrocytes in clearance, spreading and neuronal toxicity of Aβ.
  
  
  
  To examine the role of astrocytes in Aβ pathology, we added Aβ protofibrils to a co-culture system of primary neurons and glia. Our data demonstrates that astrocytes rapidly engulf large amounts of Aβ protofibrils, but then store, rather than degrade the ingested material. The incomplete digestion results in a high intracellular load of toxic, partly N-terminally truncated Aβ and severe lysosomal dysfunction. Moreover, secretion of microvesicles containing N-terminally truncated Aβ, induce apoptosis of cortical neurons.
  
  
  
  Taken together, our results suggest that astrocytes play a central role in the progression of Alzheimer's disease, by accumulating and spreading toxic Aβ species.
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Söllvander
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nikitidou
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors.forename: Robin
authors.initials: R
authors.lastname: Brolin
authors.affiliation: BioArctic Neuroscience AB, Warfvinges väg 35, SE-112 51, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Söderberg
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors.forename: Dag
authors.initials: D
authors.lastname: Sehlin
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Department of Public Health & Caring Sciences/Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden. anna.erlandsson@pubcare.uu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Erlandsson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D011992:Endosomes / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D059008:Time-Lapse Imaging
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease; Degradation; Enlarged vacuole; Glia; Microvesicle; Phagocytosis; Protofibrils