title: Amyloid β peptides promote autophagy-dependent differentiation of mouse neural stem cells: Aβ-mediated neural differentiation.
abstract: Although regarded as neurotoxic, amyloid β (Aβ) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in Aβ-mediated effects, although its precise function in neural differentiation remains unknown. Here, we addressed the role of different Aβ fragments in neural stem cell (NSC) proliferation and differentiation, and investigated whether autophagy is involved in Aβ-induced alterations of neural fate. Our results demonstrate that neuronal and glial-specific protein markers are significantly induced by both Aβ1-40 and Aβ1-42. However, Aβ1-40 preferentially enhances neurogenesis of NSCs, as determined by βIII-tubulin, NeuN, and MAP2 neuronal marker immunoreactivity, while Aβ1-42 appears to favor gliogenesis. In contrast, Aβ25-35 does not influence NSC fate. The effect of Aβ1-40 on neurogenesis is partially dependent on its role in NSC self-renewal as both S-phase of the cell cycle and BrdU labeling were markedly increased. Nevertheless, Aβ1-40 resulted also in increased Tuj1 promoter activity. Autophagy, assessed by conversion of endogenous LC3-I/II, fluorescence of pGFP-LC3-transfected cells, and Atg9 protein levels, was evident in both Aβ1-40- and Aβ1-42-treated NSCs, independently of reactive oxygen species production and apoptosis. Finally, inhibition of autophagy by pharmacologic means abrogated Aβ-induced lineage-specific protein markers. These results support distinct roles for different Aβ peptides in NSC fate decision and underline the importance of autophagy control of this process.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Fonseca
authors.forename: Susana
authors.initials: S
authors.lastname: Solá
authors.forename: Joana M
authors.initials: JM
authors.lastname: Xavier
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Dionísio
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D005333:Fetus / Q000166:cytology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology; D016196:S Phase / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C025946:3-methyladenine; D000225:Adenine