In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis.
Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.
Li
Jin-Ping
JP
Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. jin-ping.li@imbim.uu.se
Galvis
Martha L Escobar
ML
Gong
Feng
F
Zhang
Xiao
X
Zcharia
Eyal
E
Metzger
Shula
S
Vlodavsky
Israel
I
Kisilevsky
Robert
R
Lindahl
Ulf
U
D000686:Amyloidosis / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D015152:Blotting, Northern; D002851:Chromatography, High Pressure Liquid; D003224:Congo Red; D015971:Gene Expression Regulation, Enzymologic; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006651:Histocytochemistry; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D000099175:Heparanase
D003224:Congo Red; D005966:Glucuronidase; D006497:Heparan Sulfate; D000685:Serum Amyloid A Protein; D000099175:Heparanase