The long-term objective of this proposal is to determine the pathogenesis of amyloidosis and its relationship to aging and nutrition. We are postulating that the administration of casein or azocasein to amyloid susceptible mice overwhelms the proteolytic capacity of the mononuclear phagocytic system (MPS), either by inhibition of specific cell membrane associated enzymes or by activation of serine esterase inhibitors, one of which may be SAP or amyloid P component. The influence of strain, age and gender of the mouse on the incidence of amyloidosis is presumably reflected in reduced MPS protease activity which in turn can be modified by altering dietary factors, particularly and type of fat (saturated and unsaturated, omega 3 and omega 6 fatty acids) and the level of antioxidants (vitamin E). Using two models of experimental amyloidosis, i.e., 1) an acute model in which young CBA/J (susceptible) and A/J (resistant) received daily azocasein injections and 2) a chronic model in which aged C57B1/6Nia, A/J, and SJL/J mice are maintained on high casein diets, our specific aims are: first, to determine whether strain differences in susceptibility to amyloidosis are related to the ability of the MPS to degrade serum amyloid A (SAA) precursor protein or to differences in MPS production of prostaglandins or activated oxygen radicals; second, to determine if observed differences in ability of the MPS to degrade SAA can be explained by the presence of competitive substrates such as casein or by enzyme inhibitors such as SAP; third, to determine whether altering dietary factors such as the type of fatty acid and level of antioxidants can alter the incidence and severity of amyloidosis in the two models and whether such changes can be correlated with changes in MPS protease activity. The effect of dietary manipulations prior to the induction of experimental amyloidosis as well as after amyloidosis is clearly established will be studied. To achieve these aims we will utilize cell cultures of peritoneal macrophages and Kupffer cells from animals that have been maintained on different dietary and amyloid inducing protocols and compare proteolytic activity, prostaglandin profiles and production and metabolism of activated oxygen radicals. These studies should provide helpful information to aid in designing rational dietary or therapeutic regimens for intervention in the development or for the treatment of human amyloidosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006860-05
Application #
3117945
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1991-09-05
Budget End
1992-08-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Cathcart, E S; Elliott-Bryant, R (1999) Diet, amyloid enhancing factor (AEF) and amyloidogenesis: an hypothesis. Amyloid 6:107-13
Elliott-Bryant, R; Cathcart, E S (1998) Amyloid enhancing factor and dietary transmission in accelerated amyloid A amyloidosis. Clin Immunol Immunopathol 88:65-9
Elliott-Bryant, R; Liang, J S; Sipe, J D et al. (1998) Catabolism of lipid-free recombinant apolipoprotein serum amyloid A by mouse macrophages in vitro results in removal of the amyloid fibril-forming amino terminus. Scand J Immunol 48:241-7
Gruys, E; Tooten, P C; Cathcart, E S (1998) Polyarthritis and periostitis induced by Escherichia coli. Lipopolysaccharide injection in young male hamsters. J Rheumatol 25:748-52
Hajri, T; Elliott-Bryant, R; Sipe, J D et al. (1998) The acute phase response in apolipoprotein A-1 knockout mice: apolipoprotein serum amyloid A and lipid distribution in plasma high density lipoproteins. Biochim Biophys Acta 1394:209-18
Kirschner, D A; Elliott-Bryant, R; Szumowski, K E et al. (1998) In vitro amyloid fibril formation by synthetic peptides corresponding to the amino terminus of apoSAA isoforms from amyloid-susceptible and amyloid-resistant mice. J Struct Biol 124:88-98
Liang, J; Elliott-Bryant, R; Hajri, T et al. (1998) A unique amyloidogenic apolipoprotein serum amyloid A (apoSAA) isoform expressed by the amyloid resistant CE/J mouse strain exhibits higher affinity for macrophages than apoSAA1 and apoSAA2 expressed by amyloid susceptible CBA/J mice. Biochim Biophys Acta 1394:121-6
Elliott-Bryant, R; Cathcart, E S (1997) Apolipoprotein E and apolipoprotein A-1 knock-out mice readily develop amyloid A protein amyloidosis. Clin Immunol Immunopathol 85:104-8
Liang, J S; Sloane, J A; Wells, J M et al. (1997) Evidence for local production of acute phase response apolipoprotein serum amyloid A in Alzheimer's disease brain. Neurosci Lett 225:73-6
Liang, J S; Schreiber, B M; Salmona, M et al. (1996) Amino terminal region of acute phase, but not constitutive, serum amyloid A (apoSAA) specifically binds and transports cholesterol into aortic smooth muscle and HepG2 cells. J Lipid Res 37:2109-16

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