Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy.
Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.
Gervais
F
F
Neurochem Inc, St-Laurent, Quebec, Canada. fgervais@neurochem.com
Chalifour
R
R
Garceau
D
D
Kong
X
X
Laurin
J
J
Mclaughlin
R
R
Morissette
C
C
Paquette
J
J
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy* / Q000378:metabolism; D002942:Circular Dichroism; D006025:Glycosaminoglycans / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008854:Microscopy, Electron; D018716:Molecular Mimicry; D051381:Rats
D016229:Amyloid beta-Peptides; D006025:Glycosaminoglycans