Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways

Ayumi Takamura, Yota Sato, Daisuke Watabe, Yasuhide Okamoto, Takashi Nakata, Takeshi Kawarabayashi, Salvatore Oddo, Frank M. Laferla, Mikio Shoji, Etsuro Matsubara

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Aims: 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. Main 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. Key findings: 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. Significance: 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.

Original languageEnglish (US)
Pages (from-to)1177-1186
Number of pages10
JournalLife Sciences
Volume91
Issue number23-24
DOIs
StatePublished - Dec 10 2012

Keywords

  • Alzheimer's disease
  • Aβ immunotherapy
  • Aβ oligomers
  • Intraneuronal Aβ
  • Sortilin
  • Tau
  • p75NTR

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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    Takamura, A., Sato, Y., Watabe, D., Okamoto, Y., Nakata, T., Kawarabayashi, T., Oddo, S., Laferla, F. M., Shoji, M., & Matsubara, E. (2012). Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways. Life Sciences, 91(23-24), 1177-1186. https://doi.org/10.1016/j.lfs.2012.04.038