Membrane-Anchored Aβ Accelerates Amyloid Formation and Exacerbates Amyloid-Associated Toxicity in Mice

Pathological, genetic, and biochemical hallmarks of Alzheimer's disease (AD) are linked to amyloid-beta (A beta) peptide aggregation. Especially misfolded A beta(42) peptide is sufficient to promote amyloid plaque formation. However, the cellular compartment facilitating the conversion of monomeric A beta to aggregated toxic A beta species remains unknown. In vitro models suggest lipid membranes to be the driving force of A beta conversion. To this end, we generated two novel mouse models, expressing either membrane-anchored or nonanchored versions of the human A beta(42) peptide. Strikingly, membrane-anchored A beta(42) robustly accelerated A beta deposition and exacerbated amyloid-associated toxicity upon crossing with A beta precursor protein transgenic mice. These in vivo findings support the hypothesis that A beta membrane interactions play a pivotal role in early-onset AD as well as neuronal damage and provide evidence to study A beta-membrane interactions as therapeutic targets.