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Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies

Molecular neurobiology, 2021-12, Vol.58 (12), p.6647-6669 [Peer Reviewed Journal]

The Author(s) 2021 ;2021. The Author(s). ;The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 0893-7648 ;ISSN: 1559-1182 ;EISSN: 1559-1182 ;DOI: 10.1007/s12035-021-02567-8 ;PMID: 34608607

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Title:
Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies
Author: Vrancx, Céline ; Vadukul, Devkee M. ; Suelves, Nuria ; Contino, Sabrina ; D’Auria, Ludovic ; Perrin, Florian ; van Pesch, Vincent ; Hanseeuw, Bernard ; Quinton, Loïc ; Kienlen-Campard, Pascal
Subjects: Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Alzheimers disease ; Amyloid beta-Peptides ; Amyloid beta-Peptides - metabolism ; Animals ; Aβ oligomers ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Brain - metabolism ; Brain - pathology ; Catalytic subunits ; Cell Biology ; Cell culture ; Cell Line, Tumor ; Cell lines ; Cellular and Molecular Neuroscience ; Cerebrospinal fluid ; CHO Cells ; Cricetulus ; CRISPR ; FAD model ; Fibrils ; Fibroblasts ; Fibroblasts - metabolism ; Hexameric Aβ ; Human health sciences ; Humans ; Mice ; Mice, Transgenic ; Neurobiology ; Neurodegenerative diseases ; Neurologie ; Neurology ; Neurons ; Neurons - metabolism ; Neurons - pathology ; Neuroscience (miscellaneous) ; Neurosciences ; Neurotoxicity ; Pathology ; Plaque, Amyloid ; Plaque, Amyloid - metabolism ; Plaque, Amyloid - pathology ; Presenilin 1 ; Presenilin 2 ; Presenilins ; Presenilins - metabolism ; Protein seeding ; Sciences de la santé humaine ; Secretase ; Seeding ; Self-assembly ; Senile plaques ; Transgenic mice ; β-Amyloid
Is Part Of: Molecular neurobiology, 2021-12, Vol.58 (12), p.6647-6669
Description: 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.
Publisher: New York: Springer US
Language: English
Identifier: ISSN: 0893-7648
ISSN: 1559-1182
EISSN: 1559-1182
DOI: 10.1007/s12035-021-02567-8
PMID: 34608607
Source: ProQuest One Psychology
MEDLINE
SpringerOpen website
ProQuest Central

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Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies

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