Opposing actions of thrombin and protease nexin-1 on amyloid beta-peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons.
Amyloid beta-peptide (A beta) is the principal component of neuritic plaques in the brain in Alzheimer's disease (AD). Recent studies revealed that A beta can be neurotoxic by a mechanism involving free radical production and loss of cellular ion homeostasis, thus implicating A beta as a key factor in the pathogenesis of AD. However, other proteins are present in plaques in AD, including the protease thrombin and protease nexin-1 (PN1), a thrombin inhibitor. We therefore tested the hypothesis that thrombin and PN1 modify neuronal vulnerability to A beta toxicity. In dissociated rat hippocampal cell cultures the toxicity of A beta was significantly enhanced by coincubation with thrombin, whereas PN1 protected neurons against A beta toxicity. A beta induced an increase in levels of intracellular peroxides and calcium. Thrombin enhanced, and PN1 attenuated, the accumulation of peroxides and calcium induced by A beta. Taken together, these data demonstrate that thrombin and PN1 have opposing effects on neuronal vulnerability to A beta and suggest that thrombin and PN1 play roles in the pathogenesis of neuronal injury in AD.
Smith-Swintosky
V L
VL
Sanders-Brown Research Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Zimmer
S
S
Fenton
J W
JW
Mattson
M P
MP
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism*; D058255:Protease Nexins; D051381:Rats; D011956:Receptors, Cell Surface; D058258:Serpin E2; D013917:Thrombin / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D010545:Peroxides; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2; D013917:Thrombin; D002118:Calcium