Discovery of the intracellular site where pathological conformations of the toxic Alzheimer’s Aβ oligomers are formed
The research group led by Prof. Antonino Cattaneo (Head of Laboratory of Neurotrophic Factors and Neurodegenerative Diseases at EBRI, and of BioSNS Laboratory of Biology at Scuola Normale Superiore di Pisa) and by Dr. Giovanni Meli (Junior Group Leader at EBRI), in collaboration with Dr. Roberta Ghidoni (Head of Proteomics Unit at IRCCS “San Giovanni di Dio” Fatebenefratelli in Brescia) has developed a novel approach to target and to control the fate of specific toxic conformations of the peptide beta Amyloid (Aβ) in living cells, demonstrating the formation of pathological Aβ oligomers in the Endoplasmic Reticulum.
Aβ oligomers (AβOs) are toxic species crucially involved in the early events of the pathogenesis of Alzheimer’s Disease (AD). However, little was known about the intracellular formation and trafficking of AβOs before this study, for the lack of selective targeting approaches. The nature and subcellular origin of AβOs, a toxic killer of neurons, has been elusive and controversial. This discovery clarifies a new important issue.
The research team applied the “intrabody” approach, pioneered by Antonino Cattaneo in 1990, whereby recombinant antibody fragments are expressed as genes and determine a selective functional protein knock-out or interference of the protein-antigen recognized inside the cell.
This study demonstrates that the intrabody approach is an effective and selective strategy to target subcellular pools of AβOs, establishing the new concept of Conformational-Selective Interference (CSI). Targeting a conformation-sensitive intrabody selectively to the Endoplasmic Reticulum (ER), the authors demonstrate that the Aβ peptides, naturally produced by living cells, oligomerize through critical conformations formed inside this subcellular compartment.
This study establishes intracellular AβOs as key target for AD treatment and prospects the CSI approach as a potential therapeutic targeting strategy.
This work was supported by Alzheimer’s Association, Italian Ministry of University and Research (MIUR), Fondazione Roma, Human Brain Project.