Potential Protective Function of Aβ₄₂ Monomer on Tauopathies

Abstract

While soluble forms of amyloid-β (Aβ) and Tau work together to drive healthy neurons into a disease state, how their interaction may control the prion-like propagation and neurotoxicity of Tau is not fully understood. The cross-linking via disulfide bond formation is crucial for Tau oligomers to obtain stable conformers and spread between cells. This work thus focuses on how Aβ42 regulates this critical process. By studying the interactions between Aβ42 and TauPHF43, a construct that mimics the Tau R3 isoform, has a similar length to Aβ42, and contains one cysteine (Cys-322), we discovered that fresh Aβ42 could protect Tau against the formation of disulfide cross-linked dimers. We showed that the monomeric and small Aβ oligomers (the “nonamyloidogenic Aβ”) efficiently disassembled tau dimers and heparin-induced Tau oligomers to recover Tau monomers. Interestingly, Aβ serves the role of an antioxidant to prevent disulfide bond formation, as supported by the experiments of Aβ with cystine. Furthermore, using cyclosporine A (CycA), a macrocyclic β-sheet disruptor, we demonstrated that targeting amyloidogenic Aβ with CycA does not affect the TauPHF43 disassembly driven by Aβ42. Separately, we assessed the initial toxicity of Aβ42 and TauPHF43 in acute brain slices and found that Aβ42 is more toxic than TauPHF43 or the two peptides combined. Our work highlights a potential protective role of Aβ42 monomers in AD that was previously overlooked while focusing on the mechanism behind Aβ42 aggregation leading to tau dysfunction.

Investigating a Novel Neurodegenerative Disease Toxic Mechanism Involving Lipid Binding Specificity of Amyloid Oligomers

“…The toxicity of G6W and KV11 is more than that of Aβ(1−42) measured under the same condition. 31 Notably, the G6W dodecamer structurally resembles lipid transport proteins, such as the fatty acid binding protein (Figure 1B). Its structure is made up of asymmetrical, antiparallel β-sheets and contains a hydrophobic cavity that has the size and shape capable of the insertion of one 16-C fatty acid tail.…”

“…Interestingly, the toxic profile of G6W is consistent with neurodegeneration in AD; − thus, it will be used as an amyloid oligomer model for neurodegenerative diseases. The toxicity of G6W and KV11 is more than that of Aβ(1–42) measured under the same condition …”