Abstract
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.
Highlights
The β-amyloid peptide (Aβ) is the major constituent of senile plaques, a typical histological hallmark of Alzheimer's disease (AD)
The growing body of evidence pointing to the pathological properties of oligomeric—and hexameric—Aβ assemblies mostly stems from observations gathered using synthetic Aβ peptides
These studies were first carried out in CHO (Chinese hamster ovary) cells transiently transfected with vectors expressing the human sequences of either Aβ42 or βCTF (C99), each fused to the amyloid precursor protein (APP) signal peptide to ensure a proper cellular trafficking of the expressed fragments (Fig. 1a)
Summary
The β-amyloid peptide (Aβ) is the major constituent of senile plaques, a typical histological hallmark of Alzheimer's disease (AD). APP undergoes a first cleavage by β-secretase, producing a 99-amino acid membrane-bound C-terminal fragment (βCTF or C99), which in turn is cleaved by γ-secretase to generate the intracellular domain of APP (AICD) and Aβ. Different isoforms of Aβ can be produced, mostly ranging from 38 to 43 amino acids [2]. After its release as a monomer, Aβ and its longer forms such as Aβ42, has the propensity to selfassemble [3]. This leads to the formation of Aβ oligomers and amyloid fibrils, aggregating into senile plaques in the brain
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