title: Sortilin is required for toxic action of Aβ oligomers (AβOs): extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways.
abstract: OBJECTIVE
  We investigated the pathological relevance of the "Aβ oligomer (AβO) cascade hypothesis" in 3xTg-AD mice. This study was also designed to elucidate the molecular mechanism underlying the toxic action of AβOs.
  
  
  METHODS
  To target the extracellular AβOs in vivo, a monoclonal antibody specific for AβOs was developed using a novel method. Monoclonal 72D9 was intravenously administered to aged 3xTg-AD mice bearing the human AD pathology to investigate the relevance of the AβO cascade hypothesis. To further identify the AβO-binding molecule on the cell surface, small interfering RNA (siRNA) for sortilin was transfected into SH-SY5Y cells. The sortilin-dependent molecular mechanism underlying toxic action of AβOs and/or AβO endocytosis was also assessed in cultured cortical neurons forming synapses.
  
  
  RESULTS
  The 72D9 immunotherapy of aged 3xTg-AD mice revealed that extracellular and intraneuronal AβOs are related, and that intraneuronal AβOs act upstream of tau. We also found that extracellular AβOs first act as a sortilin ligand, and then induce p75(NTF)-mediated apoptosis, endocytosis-induced attenuation of autophagy, or accumulation of AβOs in autophagosomes.
  
  
  CONCLUSIONS
  Taken together, these findings provide novel lines of evidence that sortilin governs the toxic action of extracellular AβOs, which affects the degradation and/or clearance of either intraneuronal AβOs or tau. Thus, therapeutic intervention targeting extracellular AβOs themselves or for preventing the interaction between intraneuronal AβOs and tau is a promising strategy to be developed for AD treatment.
authors.affiliation: Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takamura
authors.forename: Yota
authors.initials: Y
authors.lastname: Sato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Watabe
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawarabayashi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
authors.forename: Mikio
authors.initials: M
authors.lastname: Shoji
authors.forename: Etsuro
authors.initials: E
authors.lastname: Matsubara
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008954:Models, Biological; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D034741:RNA, Small Interfering; D016875:tau Proteins; D000099183:Sortilin