Inhibitor of cyclooxygenase-2 protects against amyloid beta peptide-evoked memory impairment in mice.
Alzheimer's disease (AD) results in an impairment of memory and behavior. It is accepted that amyloid beta (A beta) peptides are responsible for the etiopathology of AD, but the precise signaling pathways leading to the disease have not been elucidated. In this study, we have investigated the role of cyclooxygenase-2 (COX-2) in A beta(1-42)-evoked memory impairment in mice. Moreover, the effect of systemic inflammation on A beta-dependent locomotor and memory disturbances has been evaluated. Twelve-month-old C57Bl6 mice were injected intracerebroventricularly (icv) with A beta(1-42) alone or simultaneously with intraperitoneal (ip) administration of lipopolysaccharide (LPS). Some mice also received COX-2 inhibitor, NS-398. Another group of mice was pretreated with LPS at 4 and 7 months of age, and then injected with A beta(1-42) at 12 months of age. All mice were subjected to behavioral tests one week after A beta administration. COX-2 protein level was analyzed in the hippocampus using immunochemical method. Our data demonstrated that A beta enhanced COX-2 protein level and decreased the locomotion and exploration in mice. Systemic inflammation elevated COX-2 immunoreactivity at an early stage after injection and intensified behavioral disturbances. Moreover, the object recognition in A beta-treated mice was significantly affected compared to control mice. The administration of LPS simultaneously with A beta worsened recognition performance. A COX-2 inhibitor protected mice against memory deficit and locomotor disturbances. In LPS-pretreated animals, A beta induced locomotor disturbances, but had no effect on memory and COX-2 level. Our results indicate that A beta evokes enhancement of COX-2 protein level and memory deficit. Systemic inflammation modulates A beta effect on the brain function. The COX-2 inhibitor protects the brain against A beta-induced memory disturbances.
Cakała
Magdalena
M
Department of Cellular Signalling, Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, PL 02-106 Warszawa, Poland. magcakala@cmdik.pan.pl
Malik
Anna R
AR
Strosznajder
Joanna B
JB
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051546:Cyclooxygenase 2