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 and death. Colocalization of heparan sulfate (HS) proteoglycans to amyloid deposits suggests that they may be an early event in amyloid formation and play an important role in fibril formation. Structural analysis has demonstrated that HS interacts with amyloidogenic proteins resulting in structural changes that allow for an increase in beta-sheet content, possibly enhancing fibrillogenesis. Recent studies have shown that small-molecule anionic sulfonates or sulfates can arrest inflammation-associated (AA) amyloid induction.


METHODS
In the present study, we examine the effect of low-molecular-weight heparins (LMWHs) on the development of amyloid in the mouse model of AA amyloid. In addition, in vitro fibril formation assays were performed to determine the effect of LMWHs on fibrillogenesis.


RESULTS
Injection of mice with clinically relevant doses of LMWHs (enoxaparin and dalteparin) demonstrated a reduction in AA amyloid deposition. These compounds were capable of arresting the progression of AA amyloid and eventually resulting in regression of the amyloid deposits. In vitro analysis indicated that LMWHs prevented AA and Abeta peptide fibril formation by impeding the structural changes necessary for fibril formation.


CONCLUSIONS
Our findings suggest that the LMWHs may provide beneficial effects against the development of amyloidoses, including Alzheimer's disease.
Zhu
H
H
Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
Yu
J
J
Kindy
M S
MS
D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002942:Circular Dichroism; D017985:Dalteparin / Q000627:therapeutic use*; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013158:Splenic Diseases / Q000188:drug therapy / Q000473:pathology
D000682:Amyloid; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D017985:Dalteparin