Membrane-anchored Aβ accelerates amyloid formation and exacerbates amyloid-associated toxicity in mice

Abstract

Pathological, genetic, and biochemical hallmarks of Alzheimer's disease (AD) are linked to amyloid-β (Aβ) peptide aggregation. Especially misfolded Aβ42 peptide is sufficient to promote amyloid plaque formation. However, the cellular compartment facilitating the conversion of monomericAβ to aggregated toxicAβ species remains unknown. In vitro models suggest lipidmembranesto be the driving force of Aβ conversion. To this end, we generated two novel mouse models, expressing either membrane-anchored or nonanchored versions of thehumanAβ42 peptide. Strikingly, membrane-anchoredAβ42 robustly acceleratedAβ deposition and exacerbated amyloidassociated toxicity upon crossing with Aβ precursor protein transgenic mice. These in vivo findings support the hypothesis that Aβ-membrane interactions play a pivotal role in early-onset AD as well as neuronal damage and provide evidence to study Aβ-membrane interactions as therapeutic targets. © 2013 the authors.