Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Abstract

Edited by Per HammarströmKeywords: Amyloidosis Transgenic model Amyloid A AL amyloid Cystatin c Gelsolin Transthyretin Alzheimer's disease Serpinopathies Familial dementias a b s t r a c tThe amyloidoses are the prototype gain of toxic function protein misfolding diseases. As such, several naturally occurring animal models and their inducible variants provided some of the first insights into these disorders of protein aggregation. With greater analytic knowledge and the increasing flexibility of transgenic and gene knockout technology, new models have been generated allowing the interrogation of phenomena that have not been approachable in more reductionist systems, i.e. behavioral readouts in the neurodegenerative diseases, interactions among organ systems in the transthyretin amyloidoses and taking pre-clinical therapeutic trials beyond cell culture. The current review describes the features of both transgenic and non-transgenic models and discusses issues that appear to be unresolved even when viewed in their organismal context.

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research

“…As the role of islet amyloidosis in the pathogenesis of type 2 diabetes is not fully understood, animal models mimicking the human situation, such as pigs with humanized IAPP, are needed. This approach appears favorable compared to existing human IAPP transgenic rodent models, excluding the formation of mixed, human/rodent IAPP aggregates that were suggested to be less pathogenic (reviewed in [126]). …”

Current and New Perspectives on the Molecular and Cellular Mechanisms of Amyloid Formation and Toxicity in Light Chain Amyloidosis

“…Buxbaum proposed that any future successful transgenic animal model of the extracellular amyloidoses should allow more precise understanding of the pathogenesis and the role of other proteins in facilitating or inhibiting amyloid generation and deposition. The use of worms (Caenorhabditis elegans) and flies (Drosophila melanogaster) to study amyloidoses has allowed the study of some disease processes, but Buxbaum argued that the relationship between the cellular and molecular phenotype and human disease may be problematic (Buxbaum, 2009). …”

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

“…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).…”

“…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).…”

“…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.…”