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

The beta-amyloid peptide (A beta) is found as amyloid fibrils in senile plaques, a typical hallmark of Alzheimer's disease (AD). However, intermediate soluble oligomers of A beta are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant A beta have shown that hexameric A beta in particular acts as a critical nucleus for A beta self-assembly. We recently isolated hexameric A beta assemblies from a cellular model, and demonstrated their ability to enhance A beta aggregation in vitro. Here, we report the presence of similar hexameric-like A beta 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 gamma-secretase complex that generates A beta. 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 A beta assemblies in extracellular vesicles. Further, we assessed the contribution of hexameric A beta to the development of amyloid pathology. We report the early presence of hexameric-like A beta assemblies in both transgenic mice brains exhibiting human A beta pathology and in the cerebrospinal fluid of AD patients, suggesting hexameric A beta as a potential early AD biomarker. Finally, cell-derived hexameric A beta was found to seed other human A beta forms, resulting in the aggravation of amyloid deposition in vivo and neuronal toxicity in vitro.

Automated summary

This study reveals the presence of hexameric-like Aβ assemblies in various cellular models, including neuronal-like cell lines. It also investigates the role of presenilin-1 and presenilin-2 in the formation of hexameric Aβ. Furthermore, the study suggests hexameric Aβ as a potential early biomarker for AD and demonstrates its ability to seed other Aβ forms, contributing to amyloid deposition in vivo and neuronal toxicity in vitro.