The region 1-11 of Alzheimer amyloid-beta is critical for activation of contact-kinin system.
Amyloid-beta protein (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and its ability to trigger a local inflammatory response. In the present study using truncated Abeta peptides, we identified the region between residues 1 and 11 as critical for the activation of the contact system in vitro through an ionic interaction of Abeta with factor XII and/or kallikrein. Concomitant incubation of a small cationic peptide (lysine(4)) with Abeta abrogated its ability to trigger the cleavage of high molecular weight kininogen, indicating that Abeta's activity can be blocked by an inhibitory peptide. These findings could be clinically important, since there is evidence that the contact system is activated in AD brain. Thus, prevention of contact system activation, beside diminishing the recruitment of glial cells and microvascular permeability, can also decrease the activation of complement system and the release of IL6, both factors being considered to play an important role in the inflammatory reactions in AD brain.
Bergamaschini
L
L
Department of Internal Medicine, Ospedale Maggiore, IRCCS, University of Milan, Italy. Luigi.Bergamaschini@unimi.it
Donarini
C
C
Foddi
C
C
Gobbo
G
G
Parnetti
L
L
Agostoni
A
A
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D005174:Factor XII / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000187:drug effects*; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism*; D007705:Kinins / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D019679:Kininogen, High-Molecular-Weight; D007705:Kinins; D010446:Peptide Fragments; C115195:amyloid beta-protein (1-11); C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C092395:amyloid beta-protein (12-28); C074636:amyloid beta-protein (25-35); D005174:Factor XII; D007610:Kallikreins