[en] The β-amyloid peptide (Aβ) is found as amyloid fibrils in senile plaques, a typical hallmark of Alzheimer's disease (AD). However, intermediate soluble oligomers of Aβ are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant Aβ have shown that hexameric Aβ in particular acts as a critical nucleus for Aβ self-assembly. We recently isolated hexameric Aβ assemblies from a cellular model, and demonstrated their ability to enhance Aβ aggregation in vitro. Here, we report the presence of similar hexameric-like Aβ assemblies across several cellular models, including neuronal-like cell lines. In order to better understand how they are produced in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in their formation. PS1 and PS2 are the catalytic subunits of the γ-secretase complex that generates Aβ. Using CRISPR-Cas9 to knockdown each of the two presenilins in neuronal-like cell lines, we observed a direct link between the PS2-dependent processing pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles. Further, we assessed the contribution of hexameric Aβ to the development of amyloid pathology. We report the early presence of hexameric-like Aβ assemblies in both transgenic mice brains exhibiting human Aβ pathology and in the cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a potential early AD biomarker. Finally, cell-derived hexameric Aβ was found to seed other human Aβ forms, resulting in the aggravation of amyloid deposition in vivo and neuronal toxicity in vitro.
Disciplines :
Neurology
Author, co-author :
Vrancx, Céline; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
Vadukul, Devkee M; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
Suelves, Nuria; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
Contino, Sabrina; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
D'Auria, Ludovic; Neurochemistry Unit, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
Perrin, Florian; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
van Pesch, Vincent; Neurochemistry Unit, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium
Hanseeuw, Bernard; Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200, Brussels, Belgium
Quinton, Loïc ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique
Kienlen-Campard, Pascal ; Alzheimer Research Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience, Université Catholique de Louvain, 1200, Brussels, Belgium. pascal.kienlen-campard@uclouvain.be
Language :
English
Title :
Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies.
FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture F.R.S.-FNRS - Fonds de la Recherche Scientifique Fondation Recherche Alzheimer FMRE - Fondation Médicale Reine Elisabeth
Funding text :
This work was supported by a grant of the Belgian F.N.R.S FRIA (Fonds National pour la Recherche Scientifique) and a grant of UCLouvain Fonds du Patrimoine to CV. Funding to PKC is acknowledged from SAO-FRA Alzheimer Research Foundation, Fondation Louvain and Queen Elisabeth Medical Research Foundation (FMRE to PKC and LQ). The work was supported by funds from FNRS Grant PDRT.0177.18 to PKC and LQ.
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