Mouse Models to Study Systemic Amyloidoses: Is Prion-Like Transmission a Common Pathogenic Mechanism?

Abstract

The amyloidoses are a group of protein-misfolding disorders characterized by the accumulation of amyloid fibrils formed from a variety of proteins. Currently, twentyeight different kinds of human and animal proteins, in intact or fragmented forms, have been found to be associated with pathological disorders such as Alzheimer’s disease, type II diabetes, prion diseases, dialysis-related amyloidosis, and various familial, senile and sporadic amyloidosis (Sipe et al., 2010; Benson et al 2008). Amyloidoses have been divided into two major classes: 1) systemic and 2) localized amyloidoses. In systemic amyloidoses, precursor proteins circulating in the blood associate to form amyloid fibrils that are then deposited throughout the body. For example, immunoglobulin light chains form deposits in patients with myeloma in AL amyloidosis. In reactive AA amyloidosis, serum amyloid A (SAA) protein forms deposits in patients with chronic inflammation, and transthyretin (TTR) forms deposits in patients with familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). Patients on long-term hemodialysis develop dialysis-related amyloidosis (DRA) due to the deposition of amyloid fibrils (As2M) of s2-microglobulin (s2m). In contrast to systemic amyloidosis, precursor proteins produced in local organs deposit in one particular area of the body in various localized amyloidoses. In mice, apolipoprotein A-II (apoA-II) in serum high density lipoproteins (HDL) forms amyloid fibrils (AApoAII) in age-associated systemic amyloidosis (senile AApoAII amyloidosis). AA amyloidosis, known as reactive or secondary amyloidosis associated with inflammation, is generally recognized as the predominant form of systemic amyloidosis that occurs in humans, mice, domestic animals and many species in the animal kingdom. These amyloidoses are characterized by the systemic deposition of extracellular fibrils composed of apoA-II in AApoAII amyloidosis or SAA (serum AA) in AA amyloidosis, primarily in the spleen, liver, heart, kidney, vessels walls, and to a lesser extent in other organs. In most