| First Author | Vrancx C | Year | 2021 |
| Journal | Mol Neurobiol | Volume | 58 |
| Issue | 12 | Pages | 6647-6669 |
| PubMed ID | 34608607 | Mgi Jnum | J:351699 |
| Mgi Id | MGI:7664270 | Doi | 10.1007/s12035-021-02567-8 |
| Citation | Vrancx C, et al. (2021) Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric beta-Amyloid Assemblies. Mol Neurobiol 58(12):6647-6669 |
| abstractText | The beta-amyloid peptide (Abeta) is found as amyloid fibrils in senile plaques, a typical hallmark of Alzheimer's disease (AD). However, intermediate soluble oligomers of Abeta are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant Abeta have shown that hexameric Abeta in particular acts as a critical nucleus for Abeta self-assembly. We recently isolated hexameric Abeta assemblies from a cellular model, and demonstrated their ability to enhance Abeta aggregation in vitro. Here, we report the presence of similar hexameric-like Abeta 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 Abeta. 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 Abeta assemblies in extracellular vesicles. Further, we assessed the contribution of hexameric Abeta to the development of amyloid pathology. We report the early presence of hexameric-like Abeta assemblies in both transgenic mice brains exhibiting human Abeta pathology and in the cerebrospinal fluid of AD patients, suggesting hexameric Abeta as a potential early AD biomarker. Finally, cell-derived hexameric Abeta was found to seed other human Abeta forms, resulting in the aggravation of amyloid deposition in vivo and neuronal toxicity in vitro. |
