In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis

Abstract

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 heparanaseoverproducing 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.inflammation ͉ transgenic mice ͉ endo-glucuronidase ͉ Congo red staining

Heparan Sulfate Dissociates Serum Amyloid A (SAA) from Acute-phase High-density Lipoprotein, Promoting SAA Aggregation

“…Several lines of evidence have demonstrated that the disease progression is dependent on HS. We have previously found that transgenic mice overexpressing human heparanase, an HS-degrading enzyme, were resistant to experimental induction of AA amyloidosis (11), demonstrating a decisive role for HS in the pathogenic process. The present study aimed to get further insight on the molecular mechanisms of the HS and SAA interaction.…”

“…Further, we have previously demonstrated that a transgenic mouse overexpressing heparanase, an HS-degrading enzyme, is resistant to experimental induction of AA amyloid (11). The overexpression of heparanase resulted in a drastic shortening of the HS chain length, demonstrating a decisive role for the polysaccharide chain length in SAA aggregation.…”

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

“…Indeed, previous studies have suggested a role for heparanase in various pathophysiological conditions, including tumor metastasis (Escobar Galvis et al, 2007;Vlodavsky and Friedmann, 2001), experimental autoimmune disease (Lider et al, 1989), amyloidosis (Li et al, 2005) and delayed type hypersensitivity (DTH) reactions . A role for heparanase in tumour metastasis is supported by the strong correlation between levels of heparanase expression and metastatic potential of B16 melanoma (Vlodavsky et al, 1999) and T lymphoma (Goldshmidt et al, 2002b) cells.…”

Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein

“…Although the precise role of HS in the pathology of amyloidosis remains unresolved, accumulating evidence suggests that HS plays an important part in amyloid deposition. Previously, we have demonstrated that amyloid A amyloidosis is correlated with HS chain length in a mouse model (15).…”