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Transthyretin (TTR) is a plasma homotetrameric protein that transports thyroxine and retinol. TTR itself, under pathological conditions, dissociates into partially unfolded monomers that aggregate and form fibrils. Metal ions such as Zn²⁺, Cu²⁺, Fe²⁺, Mn²⁺ and Ca²⁺ play a controversial role in the TTR amyloidogenic pathway. TTR is also present in cerebrospinal fluid (CSF), where it behaves as one of the major Aβ-binding-proteins. The interaction between TTR and Aβ is stronger in the presence of high concentrations of Cu²⁺. Crystals of TTR, soaked in solutions of physiological metals such as Cu²⁺ and Fe²⁺, but not Mn²⁺, Zn²⁺, Fe³⁺, Al³⁺, Ni²⁺, revealed an unusual conformational change. Here, we investigate the effects that physiological metals have on TTR, in order to understand if metals can induce a specific and active conformation of TTR that guides its Aβ-scavenging role. The capability of certain metals to induce and accelerate its amyloidogenic process is also discussed.