Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis.
Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C. & Selkoe, D. J. (1993) Cell 75, 1039-1042] and type II diabetes mellitus [Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. (1994) Nature (London) 368, 756-760]. The fibrils themselves are relatively resistant to proteolysis in vitro but amyloid deposits do regress in vivo, usually with clinical benefit, if new amyloid fibril formation can be halted. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits, including the plaques, amorphous amyloid beta protein deposits and neurofibrillary tangles of Alzheimer disease [Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., van Duinen, S., Shelanski, M. L. & Frangione, B. (1988) Lab. Invest. 58, 454-458; Duong, T., Pommier, E. C. & Scheibel, A. B. (1989) Acta Neuropathol. 78, 429-437]. Here we show that SAP prevents proteolysis of the amyloid fibrils of Alzheimer disease, of systemic amyloid A amyloidosis and of systemic monoclonal light chain amyloidosis and may thereby contribute to their persistence in vivo. SAP is not an enzyme inhibitor and is protective only when bound to the fibrils. Interference with binding of SAP to amyloid fibrils in vivo is thus an attractive therapeutic objective, achievement of which should promote regression of the deposits.
Tennent
G A
GA
Immunological Medicine Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Lovat
L B
LB
Pepys
M B
MB
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism*; D002918:Chymotrypsin / Q000378:metabolism; D005690:Galactose / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D016874:Neurofibrillary Tangles / Q000378:metabolism; D011485:Protein Binding; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000685:Serum Amyloid A Protein; C034485:4,6-pyruvylated galactose; D002918:Chymotrypsin; D014357:Trypsin; D005690:Galactose