Suppression of nuclear factor kappa B ameliorates astrogliosis but not amyloid burden in APPswe/PS1dE9 mice.
Neuroinflammation has been linked to the pathologies of Alzheimer's disease (AD), however, its effects on beta-amyloid (Abeta) burden are unclear. This study investigated the role of nuclear factor kappa B (NF-kappaB) in regulating neuroinflammation and Abeta deposition in a transgenic mouse model of AD. The APPswe/PS1dE9 mice and their wild-type controls received either the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC, i.p. 50 mg/kg daily) or saline starting at 7 months of age for 5 months. Expression of cyclooxygenase-2 (COX-2), tissue necrosis factor alpha (TNFalpha) precursor protein and microtubule-associated protein 2 was determined, and astrogliosis was assessed. Hippocampal and cortical levels of Abeta(1-40) and Abeta(1-42) were measured using ELISA. PDTC treatment effectively suppressed NF-kappaB signaling in APPswe/PS1dE9 mice as evidenced by the abolishment of COX-2 and TNFalpha induction. Inhibition of NF-kappaB further attenuated astrogliosis in the transgenic AD mice, yet markedly increased cerebral Abeta(1-42) burden. Our findings suggest that NF-kappaB can mediate induction of COX-2, TNFalpha and astrogliosis in APPswe/PS1dE9 mice. Additionally, these results support the idea that neuroinflammation contributes to the clearance of Abeta.
Zhang
X
X
Division of Pharmaceutical Sciences and Graduate Neuroscience Program, University of Wyoming, College of Health Sciences, Department 3375, 1000 East University Avenue, Laramie, WY 82071-3375, USA.
Luhrs
K J
KJ
Ryff
K A
KA
Malik
W T
WT
Driscoll
M J
MJ
Culver
B
B
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011498:Protein Precursors / Q000096:biosynthesis; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D013859:Thiocarbamates / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D016328:NF-kappa B; D011498:Protein Precursors; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2