Dissection Of The Interplay Among The Motifs Within Amyloid Beta Peptide In Processes Of Membrane Insertion And Oligomerization

Alzheimer’s disease (AD) is the most common form of dementia in which amyloid beta peptide (AP) with a length of39-42a.a. is recognized as one of the key pathological factors. The most prominent characteristics of Aβ is the strong propensity to aggregate leading to neurotoxicity. Emerging evidence indicate that instead of the higher order aggregate such as mature fibre, the soluble, low molecular weight oligomer of Aβ is the major toxic entity. In addition, Aβ can insert membrane and form intra-membrane oligomer resulting in neuronal dysfunction. In the current study, we have investigated how the motifs within Aβ sequence contribute to the two different processes, i.e. soluble oligomerization and membrane insertion, by comparing the behavior of a panel of Aβ truncation variants, including Aβ1-42, Aβ1-40, Aβ1-36, Aβ1-28, Aβ11-42and Aβ17-42. Our results reveal a complex interplay among the short motifs within Aβ. Specifically, a common initiating event appears to be shared by the soluble oligomerization and membrane insertion or intra-membrane oligomerization, i.e. overcoming the auto-inhibition conferred by the interaction between a.a.29-36and the N-terminal portion through the action of a.a.37-40/42albeit via different mechanisms. This releases Aβ into a state permissive for soluble self-assembly or stable membrane attachment. However, distinct pathways then ensue for extra-and intra-membrane oligomerization, as exemplified by their differential requirement for a.a.11-16. Indeed, this motif is exclusively required for the formation of stable intra-membrane oligomers but seems to be somewhat dispensable in the extra-membrane self-assembly. These results may provide clues for designing stage-specific and AP-targeted therapy.