Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease.
Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.
Kisilevsky
R
R
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Lemieux
L J
LJ
Fraser
P E
PE
Kong
X
X
Hultin
P G
PG
Szarek
W A
WA
D000208:Acute Disease; D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity; D000544:Alzheimer Disease / Q000188:drug therapy; D000686:Amyloidosis / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000838:Anions; D002908:Chronic Disease; D006018:Glycols / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D006497:Heparan Sulfate / Q000494:pharmacology; D051379:Mice; D011145:Polyvinyls / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013154:Spleen / Q000473:pathology; D013431:Sulfates / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity
D000476:Alkanesulfonates; D000838:Anions; D006018:Glycols; D006497:Heparan Sulfate; D011145:Polyvinyls; D000685:Serum Amyloid A Protein; D013431:Sulfates