Inhibition of amyloidosis using low-molecular-weight heparins

Background: Amyloid diseases are characterized by the tissue deposition of extracellular proteinaceous material, which results in organ dysfunction an d death. Colocalization of heparan sulfate (HS) proteoglycans to amyloid de posits suggests that they may be an early event in amyloid formation and pl ay an important role in fibril formation. Structural analysis has demonstra ted that HS interacts with amyloidogenic proteins resulting in structural c hanges that allow for an increase in P-sheet content, possibly enhancing fi brillogenesis. Recent studies have shown that small-molecule anionic sulfon ates or sulfates can arrest inflammation-associated (AA) amyloid induction. Materials and Methods: In the present study, we examine the effect of low-m olecular-weight heparins (LMWHs) on the development of amyloid in the mouse model of AA amyloid. In addition, in vitro fibril formation assays were pe rformed to determine the effect of LMWHs on fibrillogenesis. Results: Injection of mice with clinically relevant doses of LMWHs (enoxapa rin and dalteparin) demonstrated a reduction in AA amyloid deposition. Thes e compounds were capable of arresting the progression of AA amyloid and eve ntually resulting in regression of the amyloid deposits. In vitro analysis indicated that LMWHs prevented AA and A beta peptide fibril formation by im peding the structural changes necessary for fibril formation. Conclusions: Our findings suggest that the LMWHs may provide beneficial eff ects against the development of amyloidoses, including Alzheimer's disease.