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

Life Sciences
Ayumi TakamuraEtsuro Matsubara

Abstract

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. 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. 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. Taken together, these findings provide novel lines of evidence that sortilin governs the tox...Continue Reading

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Jul 22, 2014·Alzheimer's Research & Therapy·William F GoureFranz Hefti
Jun 16, 2015·Frontiers in Cellular Neuroscience·Sergio T FerreiraFernanda G De Felice
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Jul 10, 2016·Journal of Alzheimer's Disease : JAD·Carl-Henrik AnderssonPetronella Kettunen

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