Amyloidosis is a disorder characterized by extracellular fibrillar deposits of misfolded
proteins. The
amyloid deposits commonly contain several non-fibrillar
proteins as
amyloid-associated
proteins, but their roles in
amyloidosis pathology are still unknown. In mouse senile
amyloidosis,
apolipoprotein A-II (
ApoA-II) forms extracellular
amyloid fibril (AApoAII) deposits with other
proteins (AApoAII-associated
proteins) in many organs. We previously reported that R1.P1-Apoa2c mice provide a reproducible model of AApoAII
amyloidosis. In order to investigate the sequential alterations of AApoAII-associated
protein, we performed a proteomic analysis of
amyloid fibrils extracted from mouse liver tissues that contained different levels of AApoAII deposition. We identified 6 AApoAII-associated
proteins that constituted 20 of the top-ranked
proteins in mice with severe AApoAII deposition. Although the amount of AApoAII-associated
proteins increased with the progression of
amyloidosis, the relative abundance of AApoAII-associated
proteins changed little throughout the progression of
amyloidosis. On the other hand, plasma levels of these
proteins showed dramatic changes during the progression of
amyloidosis. In addition, we confirmed that AApoAII-associated
proteins were significantly associated with lipid metabolism based on functional enrichment analysis, and
lipids were co-deposited with AApoAII fibrils from early stages of development of
amyloidosis. Thus, these results demonstrate that
lipoproteins are involved in AApoAII
amyloidosis pathology.
SIGNIFICANCE: This study presented proteomic profiles of AApoAII
amyloidosis during
disease progression and it revealed co-deposition of
lipids with AApoAII deposits based on functional analyses. The relative abundance of AApoAII-associated
proteins in the
amyloid fibril fractions did not change over the course of development of AApoAII
amyloidosis pathology. However, their concentrations in plasma changed dramatically with progression of the disease. Interestingly, several AApoAII-associated
proteins have been found as constituents of
lipid-rich lesions of other degenerative diseases, such as
atherosclerosis and
age-related macular degeneration. The common
protein components among these diseases with
lipid-rich deposits could be accounted for by a
lipoprotein retention model.