Novel Disassembly Mechanisms of Sigmoid Aβ42 Protofibrils by Introduced Neutral and Charged Drug Molecules

Alzheimer’s disease (AD) is characterized by fibrillar deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles of Tau proteins. Aβ peptides are composed of 37 to 49 residues, in which the Aβ42 isoform is particularly toxic and aggregation-prone and is enriched in the plaques of AD brains and thus considered central to the development of AD. Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aβ aggregation. Here we capture the atomic-level details of the interactions between sigmoid Aβ42 fibril 2MXU/5KK3 and either natural tanshinone compounds TS1/TS0 or negative charged ER, proposing two unprecedented disassembly mechanisms. Natural TS1/TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation, destroying the ordered growth of subsequent monomers along the fibril axis. For the more compact two-fold 5KK3, attachment of TS1/TS0 at the surface including some in...