Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles
| Autor: | Roberto Furlan, Dacia Dalla Libera, Ana Ruiz, Michela Matteoli, Alessandra Bergami, Giuseppe Legname, Claudia Verderio, G. Comi, Paola Giussani, P. Joshi, Giuseppe Magnani, Roberta Ghidoni, Luisa Benussi, Elena Turola |
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| Přispěvatelé: | Joshi, P, Turola, E, Ruiz, A, Bergami, A, Libera, Dd, Benussi, L, Giussani, P, Magnani, G, Comi, Giancarlo, Legname, G, Ghidoni, R, Furlan, R, Matteoli, M, Verderio, C. |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cell Survival Interleukin-1beta microglia Biology Alzheimer Disease Extracellular medicine Animals Humans PrPC Proteins Transport Vesicles Molecular Biology Neuroinflammation Cells Cultured Neurons Original Paper Amyloid beta-Peptides Microglia Tumor Necrosis Factor-alpha Neurodegeneration Neurotoxicity Cell Biology Alzheimer's disease medicine.disease Microvesicles Peptide Fragments Cell biology Rats extracellular microvesicles Abeta 1-42 prion protein bioactive lipids medicine.anatomical_structure Biochemistry Solubility Tumor necrosis factor alpha Female Excitatory Amino Acid Antagonists |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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