title: Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles.
abstract: Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Aβ species, rather than insoluble fibrils, are the most toxic forms of Aβ. Preventing soluble Aβ formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Aβ species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Aβ forms trafficked to MVs after Aβ internalization into microglia. MV neurotoxicity was neutralized by the Aβ-interacting protein PrP and anti-Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.
authors: 1] Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy [2] Department of Medicine, CNR Institute of Neuroscience, via Vanvitelli 32, Milano 20129, Italy.
authors: P
authors: P
authors: Joshi
authors: 1] Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy [2] Department of Medicine, CNR Institute of Neuroscience, via Vanvitelli 32, Milano 20129, Italy.
authors: E
authors: E
authors: Turola
authors: Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy.
authors: A
authors: A
authors: Ruiz
authors: INSPE, Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy.
authors: A
authors: A
authors: Bergami
authors: INSPE, Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy.
authors: D D
authors: DD
authors: Libera
authors: Proteomics Unit, IRCCS Istituto centro San Giovanni di Dio Fatebenefratelli, via Pilastroni, Brescia 4 25125, Italy.
authors: L
authors: L
authors: Benussi
authors: Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy.
authors: P
authors: P
authors: Giussani
authors: INSPE, Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy.
authors: G
authors: G
authors: Magnani
authors: INSPE, Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy.
authors: G
authors: G
authors: Comi
authors: SISSA, Department of Neuroscience, Via Bonomea 265, Trieste I-34136, Italy.
authors: G
authors: G
authors: Legname
authors: Proteomics Unit, IRCCS Istituto centro San Giovanni di Dio Fatebenefratelli, via Pilastroni, Brescia 4 25125, Italy.
authors: R
authors: R
authors: Ghidoni
authors: INSPE, Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy.
authors: R
authors: R
authors: Furlan
authors: 1] Department of Biotechnology and Translational Medicine, University of Milano, via Vanvitelli 32, Milano 20129, Italy [2] IRCCS Humanitas,via Manzoni 56, Rozzano 20089, Italy.
authors: M
authors: M
authors: Matteoli
authors: 1] Department of Medicine, CNR Institute of Neuroscience, via Vanvitelli 32, Milano 20129, Italy [2] IRCCS Humanitas,via Manzoni 56, Rozzano 20089, Italy.
authors: C
authors: C
authors: Verderio
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D018621:PrPC Proteins / Q000378:metabolism; D051381:Rats; D012995:Solubility; D022161:Transport Vesicles / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D053583:Interleukin-1beta; D010446:Peptide Fragments; D018621:PrPC Proteins; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)