. Correction to: Impaired adult neurogenesis is an early event in Alzheimer's disease neurodegeneration, mediated by intracellular Aβ oligomers. Cell Death Differ. 2020 Jan 2; PubMed.

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  1. This paper presents an important strategy for conformationally selective targeting of misfolded proteins in vivo. The authors show in a Tg2576 mouse model that impairment of SVZ adult neurogenesis is an early event in the progression of neurodegeneration. This correlates well with recent findings demonstrating reduced adult neurogenesis in the brains of Alzheimer's disease patients (Mar 2019 news; May 2019 news) and enables study of the mechanisms involved in this early deficit.

    Using an intrabody approach pioneered by the Cattaneo lab, Scopa et al. exploit a recombinant nanobody that is highly selective for Aβ oligomers (Meli et al. 2009) through a conformational selective interference (CSI) strategy (Meli et al. 2014; and coverage to conference SfN 2015). 

    Here, the intrabody is expressed with a viral vector in the endoplasmic reticulum of SVZ stem cells in vitro and in vivo to block intracellular Aβ oligomers. By doing so, the authors restore adult neurogenesis to control levels, formally demonstrating a cell-autonomous mechanism that involves Aβ oligomers in the endoplasmic reticulum.

    From this well-executed and controlled study, we learn that intracellularly formed Aβ oligomers play a causal role in the observed adult neurogenesis deficits and therefore represent an important target for early intervention.

    More generally, from a methodological point of view, the paper highlights the importance of intrabody approaches to target selectively misfolded proteins in the intracellular compartments where they are first formed and exert cell-autonomous damages.

    The paper also underscores the fact that targeting intracellular misfolded proteins allows an earlier intervention, as opposed to current approaches that target tau and Aβ forms in the extracellular space. The uses of conformational and post-translational specific intrabodies (Cattaneo and Chirichella, 2018) appears to be a very promising strategy to be pursued.

    References:

    . Direct in vivo intracellular selection of conformation-sensitive antibody domains targeting Alzheimer's amyloid-beta oligomers. J Mol Biol. 2009 Apr 3;387(3):584-606. PubMed.

    . Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum. Nat Commun. 2014 May 27;5:3867. PubMed.

    . Targeting the Post-translational Proteome with Intrabodies. Trends Biotechnol. 2019 Jun;37(6):578-591. Epub 2018 Dec 18 PubMed.

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