CELLULAR METABOLISM OF AMYLOID PROTEINS IN AGING

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The overall objective is to define the natural history of spontaneous amyloidosis in hamsters and the cellular impairments of protein degradation that are common to age-associated amyloidoses. The aging golden Syrian hamster exhibits a striking gender difference in life span and in susceptibility to amyloid A (AA) fibril formation and deposition, with 100% incidence in female hamsters by 1.5 years, but only 25% in male hamsters at 3 years. In addition, female, but not male, hamsters have high concentrations of the amyloid P (AP) component analogue female protein (FP). Amyloidosis is the endpoint of a sequence of events in which SAA is transported by high density lipoprotein (HDL) through the bloodstream to peripheral tissues and incompletely degraded by mononuclear phagocytes, resulting in an exponential accumulation of AA fibrils in extracellular spaces. It is not known whether extracellular dissociation of apoSAA from HDL plays a critical role in amyloidosis, or whether SAA gene expression and AP secretion influence macrophage capacity for SAA proteolysis. It is postulated that there is a causal relationship between the pentraxin FP and impaired degradation of the AA fibril precursor serum amyloid A (SAA). Specifically, we will determine: 1) Whether the development of AA amyloidosis with aging is correlated with plasma FP concentrations a) in male and female amyloidosis-susceptible Syrian hamsters and amyloidosis- resistant Armenian hamsters b) in young and old hamsters in which amyloidosis is experimentally induced by dietary or subcutaneously injected casein; 2) Whether the degradation of SAA a) is restricted to cells of the mononuclear phagocyte series or occurs in cells of other lineages b) occurs intracellularly following uptake of SAA/HDL or apoSAA or c) is a function of the physicochemical form of SAA (SAA/HDL complex v. apoSAA) or the isotype structure of apoSAA; 3) Whether the capacity of mononuclear phagocytes to completely digest SAA is a) related to hamster strain, age and the concentration of FP in plasma b) affected by the FP or SAA gene expression c) directly or indirectly altered by FP. These studies will provide fundamental knowledge for logical therapeutic intervention in human amyloidosis and for enhancement of host defense with aging.