Abstract:

The term “amyloidosis” today refers to diseases in which amyloidogenic proteins deposit as insoluble fibrils in many tissues and organs. Thus far, many in vivo observations revealed that amyloid deposits contain, besides protein fibrils, carbohydrate and other protein components derived from intra- and extracellular spaces. These non-amyloid components may be involved in the pathogenesis and pathology of amyloidosis, such as amyloid formation and amyloid-induced tissue damage. In the 1980s, Snow and Kisilevsky found that glycosaminoglycans (GAGs) were associated with tissue amyloid deposits. They identified the GAG as heparan sulfate (HS), which is a component of heparan sulfate proteoglycan (HSPG) and a member of the GAG family. HS is now known to be associated with different types of amyloid in systemic and localized amyloidoses. From this perspective, we will discuss here the possible roles of HS and its highly sulfated domains in the pathogenesis and pathology of amyloidosis. As described above, HSulf-1 and HSulf-2 degraded RB4CD12 epitopes that had accumulated in amyloid plaques of AD modelmice. HSulf-1 and HSulf-2 also interfered with the cellular interaction and cytotoxicity of apoA-I fibrils. An ex vivo study showed that amyloid plaques were retained after degradation of RB4CD12 epitopes, so whether these “post-treated” amyloid plaques areunstable or vulnerable to proteolytic degradation and/or microglial clearance requires clarification. These results suggest a novel concept that enzymatic remodeling of HS may be a therapeutic strategy for systemic and localized amyloidoses. We previously showed that sulfate moieties of HS affected cytotoxicity and degradation of amyloid or amyloidogenic proteins by regulating their cellular interactions. Additional studies to elucidate the roles of highly sulfated domains of HS in amyloid formation, interaction of amyloid with cells in various tissues and organs, and subsequent cytotoxicity or degradation are ongoing.