Transthyretin Amyloidosis in Aged Vervet Monkeys, as a Candidate for the Spontaneous Animal Model of Senile Systemic Amyloidosis

Abstract

Transthyretin (TTR) amyloidosis is classified into systemic senile amyloidosis (SSA), due to senescent events caused by the wild type TTR gene, and familial amyloidotic cardiomyopathy (FAC) and familial amyloidotic polyneuropathy (FAP), which are inherited diseases caused by mutant TTR genes (Ando et al., 2005; Buxbaum, 2009; Rapezzi et al., 2010). TTR is biochemically stable as a tetramer; however unstable as a monomer when the amyloid fibrillogenesis is higher (Damas et al., 2005). Non-fibrillar TTR deposits can be first detected immunohistochemically in the heart of humans with SSA, and finally in the peripheral nerves of those with FAP. After the non-fibrillar TTR deposits, congophilic and/or fibrillar amyloids consisting of TTR can be detected and are consistent with immunopositive lesions for TTR (Damas et al., 2005; Sousa et al., 2002). Although animal models of SSA and FAP are strong tools to develop therapeutic agents and diagnostic materials, as well as to understand the pathomechanism (Buxbaum, 2009), spontaneous TTR amyloidosis has not yet been reported in animals. Therefore, a model has been developed using transgenic (Tg) techniques, such as Tg mice and rats with human mutant TTR genes (Buxbaum, 2009; Ueda et al., 2007). However, these model rodents do not show enough phenotypes resembling the clinical signs and histopathological features of SSA and FAP. In histopathological examinations, some Tg rodents tended to be hardly detected with fibrillar amyloid deposits, even if they reveal abundant non-fibrillar TTR immunoreactivity. Nakamura et al. (2008) observed SSA in an aged vervet monkey that showed typical clinical symptoms and histopathological features, as well as the human form of SSA. Furthermore, another group followed up on our findings (Chambers et al., 2010). Both cases revealed not only non-fibrillar TTR immunoreactivity but also fibrillar amyloid deposits. Thus, since the vervet monkey shows more mature TTR amyloid formation than Tg rodents, it could be a novel animal model for TTR amyloidosis.