title: Conformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum.
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.
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143 Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meli
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143 Roma, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Lecci
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143 Roma, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Manca
authors.affiliation: 1] European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143 Roma, Italy [2] Scuola Normale Superiore, Piazza dei Cavalieri, 7, 56126 Pisa, Italy.
authors.forename: Nina
authors.initials: N
authors.lastname: Krako
authors.affiliation: IRCCS 'Centro S.Giovanni di Dio-Fatebenefratelli', Via Pilastroni, 4, 25125 Brescia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Albertini
authors.affiliation: IRCCS 'Centro S.Giovanni di Dio-Fatebenefratelli', Via Pilastroni, 4, 25125 Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: IRCCS 'Centro S.Giovanni di Dio-Fatebenefratelli', Via Pilastroni, 4, 25125 Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: 1] European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143 Roma, Italy [2] Scuola Normale Superiore, Piazza dei Cavalieri, 7, 56126 Pisa, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008954:Models, Biological; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D051381:Rats; D057127:Single-Chain Antibodies / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D057127:Single-Chain Antibodies