Cryo-EM structure of Amyloid-β and Transthyretin complex and its implications for neuroprotective in neuroblastoma cell lines.

Alzheimer's disease is a severe neurological disorder and the most prevalent form of dementia, characterized by cognitive impairment and hypomnesia. The accumulation and aggregation of Amyloid-β peptides are central to AD pathology, triggering neuroinflammation and neuronal cell death. This study aims to investigate the molecular mechanisms underlying Aβ aggregation and its impact on neuronal function, and to explore potential therapeutic strategies, including peptide-based small molecules, for AD. We analyzed the role of Aβ in neuroinflammation and mitochondrial dysfunction using various in vitro and in vivo models. Structural characterization of the Aβ-TTR complex was performed using cryo-electron microscopy to understand the molecular interactions involved. The study reveals that Aβ aggregation leads to the activation of microglia, increased production of reactive oxygen species, and mitochondrial dysfunction, which contribute to neurodegeneration. Peptide-based small molecules demonstrated high specificity in binding to Aβ, inhibiting its aggregation, and reducing cytotoxicity in neuroblastoma cell lines. The TTR peptide (P2) effectively prevented Aβ-induced cytotoxicity and apoptosis by modulating oxidative stress and mitochondrial dynamics. Structural analysis using cryo-electron microscopy identified key interactions between Aβ and TTR, providing insights into their biological activity. The findings highlight the critical role of Aβ aggregation in AD pathogenesis and underscore the potential of peptide-based small molecules as therapeutic candidates. Understanding the structural mechanisms of Aβ and TTR interactions offers new avenues for developing strategies to prevent neurodegeneration and manage AD more effectively.