Zn(II)-Driven Impact of Monomeric Transthyretin on Amyloid-beta Amyloidogenesis

Extracellular accumulation of amyloid-beta (Abeta) peptides in the brain plays a significant role in the development of Alzheimer's disease (AD). While the co-localization and interaction of proteins and metal ions with Abeta in extracellular milieu are established, their precise pathogenic associations remain unclear. Here we report the impact of Zn(II) on the anti-amyloidogenic properties of monomeric transthyretin (M-TTR), which coexists spatially with Abeta and Zn(II) in extracellular fluids. Our findings demonstrate the Zn(II)-promoted ternary complex formation involving M-TTR, Abeta40, and Zn(II) as well as M-TTR's proteolytic activity towards Abeta40. These interactions alter the inhibitory effect of M-TTR on Abeta40 amyloidogenesis, particularly affecting the primary nucleation process, and mitigate the cytotoxicity induced by Abeta40. This study unveils the variable activities of M-TTR towards Abeta40, driven by Zn(II), providing insights into how metal ions influence the entanglement of M-TTR in the Abeta-related pathology linked to AD.