Potential Protective Function of Aβ₄₂ Monomer on Tauopathies

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 Tau_PHF43, 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 Tau_PHF43 disassembly driven by Aβ₄₂. Separately, we assessed the initial toxicity of Aβ₄₂ and Tau_PHF43 in acute brain slices and found that Aβ₄₂ is more toxic than Tau_PHF43 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.