Conformational targeting of intracellular A' 2 oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum

Giovanni Meli, Agnese Lecci, Annalisa Manca, Nina Krako, Valentina Albertini, Luisa Benussi, Roberta Ghidoni, Antonino Cattaneo

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A' 2 oligomers (A' 2Os) are crucially involved in Alzheimer's Disease (AD). However, the lack of selective approaches for targeting these polymorphic A' 2 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 A' 2Os in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of A' 2Os produced in an AD-relevant cell model, without interfering with the maturation and processing of the A' 2 precursor protein. The anti-A' 2Os intrabody selectively intercepts critical A' 2O conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular A' 2 undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular A' 2Os as key targets for AD treatment and presents CSI as a potential targeting strategy.

Original languageEnglish
Article number3867
JournalNature Communications
Publication statusPublished - May 27 2014


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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