Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum

Giovanni Meli, Agnese Lecci, Annalisa Manca, Nina Krako, Valentina Albertini, Luisa Benussi, Roberta Ghidoni and Antonino Cattaneo ()
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Giovanni Meli: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64
Agnese Lecci: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64
Annalisa Manca: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64
Nina Krako: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64
Valentina Albertini: IRCCS ‘Centro S.Giovanni di Dio-Fatebenefratelli’, Via Pilastroni, 4
Luisa Benussi: IRCCS ‘Centro S.Giovanni di Dio-Fatebenefratelli’, Via Pilastroni, 4
Roberta Ghidoni: IRCCS ‘Centro S.Giovanni di Dio-Fatebenefratelli’, Via Pilastroni, 4
Antonino Cattaneo: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64

Nature Communications, 2014, vol. 5, issue 1, 1-17

Abstract: Abstract Aβ oligomers (AβOs) are crucially involved in Alzheimer’s Disease (AD). However, the lack of selective approaches for targeting these polymorphic Aβ assemblies represents a major hurdle in understanding their biosynthesis, traffic and actions in living cells. Here, we established a subcellularly localized conformational-selective interference (CSI) approach, based on the expression of a recombinant antibody fragment against AβOs in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of AβOs produced in an AD-relevant cell model, without interfering with the maturation and processing of the Aβ precursor protein. The anti-AβOs intrabody selectively intercepts critical AβO conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular Aβ undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular AβOs as key targets for AD treatment and presents CSI as a potential targeting strategy.

Date: 2014
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DOI: 10.1038/ncomms4867

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