Research Project
Grant-in-Aid for Scientific Research (C)
Background Inflammation is one pathological change in Alzheimer (AD) brain and closely related to activation of microglia which can clear amyloid beta protein (Ab) and/or muse neurodegeneration. Our group demonstrated that NSAID (ibuprofen) suppresses amyloid pathology in Alzheimer model mice, that is confirmed by more than 11 in vivo studies. We previously showed that ibuprofen suppressed levels of IL-lb and al-antichymohypsin. On the other hand, amyloid pathology in APP Tg mice is also reduced by Ab vaccination. Vaccination which caused brain inflammation in a clinical trial is pro-infammatory and activates microglia, one potential anti- AD mechanism of vaccination. Both NSAID and Ab vaccination suppress amyloid pathology but have contrasting effects on inflammation. This possible conflict between NSAID and Ab vaccine was addressed in this study.Results Ibuprofen levels in APP Tg mice (TG2576) fed with 375ppm ibuprofen in diet, which has been shown to suppress amyloid burden (-55.9%) … More were measured. Ibuprofen levels in plasma, liver and brain were 47.04+5.17uM which was dose to the therapeutic window of rheumatoid patients, 14361-L80uM and 4.07+2.03uM which is above the COX inhibition IC50 in whole blood assays. These results suggested that ibuprofen in this dose have anti-infammatory effects. Multiple microglial markers were evaluated. CD11b and CD11c immunoreactivity per amyloid plaque in APP Tg mice were not suppressed by ibuprofen. Though amyloid burden which can stimulate microglia was suppressed, global mRNA levels of CD11b, CD11c, CD68 (macrosialin) nor iNOS in cortex were not suppressed by ibuprofen. In primary cultured microglia cells, 5-50uM ibuprofen inhibited COX activity, but did not suppress mRNA levels of CD11b, CD11c and CD68. At extremely high level of ibuprofen (500uM) suppressed the expression levels of CD11c and CD11b mRNA. These data suggested that middle or high dose of ibuprofen suppress inflammation without disturbance of microglia activation.Conclusion In vivo and in vitro data suggested that 375ppm in diet ibuprofen suppresses amyloid pathology but does not disturb microglia activation which can clear Ab. There is no evidence to show a real conflict between ibuprofen and Ab vaccine. Less
All 2007 2006
All Journal Article (21 results) (of which Peer Reviewed: 9 results) Presentation (8 results)
J Neurosci 27(52)
Pages: 14299-307
J Lipid Res. 48(11)
Pages: 2485-98
JNeurosci 27(52)
J Lipid Res 48(11)
J Neurosci 27
Pages: 14299-14307
J Lipid Res. 48
Pages: 2485-2498
Psychogeriatrics 6(1)
10019375931
Psychiatry Clin Neurosci 60 Suppl
Biochemistry. 45(15)
Biochem Biophys Res Commun. 344(2)
Nat Neurosci. 9(2)
Pages: 1-3
Psychiatry Clin Neurosci 60,1
Pages: 527-33
Biochemistry 45(15)
Pages: 4907-14
Biochem BiophysReCommun 344(2)
Pages: 525-30
Nat Neurosci 9(2)
Pages: 234-42
Psychogeriatrics 6 (1)
Psychiatry Clin Neurosci. 60 Suppl 1
Biochemistry 45 (15)
Pages: 4907-4914
Biochem Biophys Res Commun 344(2)
Pages: 525-530
Nat Neurosci. 9 (2)
Pages: 234-242
