Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-beta in vitro.
Amyloid-beta protein (Abeta) is implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and the ability to trigger local inflammation. Compounds that interact with the amino acids of the N-terminal region or interfere with aggregation can reduce the Abeta biologic activity. We evaluated the effect of heparin on Abeta (1-42) neurotoxicity and on its ability to activate complement and contact system. On differentiated PC12 cells, a reliable model of neuronal cells, heparin at the doses of 10 and 20 microg/ml significantly counteracted Abeta cytotoxicity as assessed by measuring MTT conversion. We then explored the effect of heparin on Abeta (1-42)-induced complement and contact system activation. Abeta (1-42) was incubated with heparin in presence of normal plasma as the source of complement and contact system factors. Heparin reduced, in a dose-dependent manner, complement and contact system activation, assessed by measuring the degree of C4 and high molecular weight kininogen cleavage. The present data show that heparin can attenuate neurotoxic and pro-inflammatory activity of Abeta and suggest that this drug could represent a new strategy to reduce the progressive neurodegeneration in AD.
Bergamaschini
Luigi
L
Department of Internal Medicine, Ospedale Maggiore IRCCS, University of Milan, Italy. Luigi.Bergamaschini@unimi.it
Donarini
Cesare
C
Rossi
Emanuela
E
De Luigi
Ada
A
Vergani
Carlo
C
De Simoni
Maria Grazia
MG
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000633:toxicity*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects; D003720:Densitometry; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000633:toxicity; D051381:Rats
D016229:Amyloid beta-Peptides; D000925:Anticoagulants; D007202:Indicators and Reagents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006493:Heparin