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

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.