Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

<p>Abstract</p> <p>Background</p> <p>Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified <it>R</it>-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic <it>R</it>-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice.</p> <p>Results</p> <p>A four-month preventative treatment regimen with <it>R</it>-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of <it>R</it>-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning.</p> <p>Conclusion</p> <p>We have found that chronic administration of <it>R</it>-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Aβ42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of <it>R</it>-flurbiprofen as an AD therapeutic and its possible mechanisms of action.</p

Out FOXing Parkinson Disease: Where Development Meets Neurodegeneration

The central survival role of FOX proteins may allow a unified view of the genetic and environmental factors that cause Parkinson disease

On-line estimation of O2 production, CO2 uptake, and growth kinetics of microalgal cultures in a gas-tight photobioreactor

Growth of the green algae Chlamydomonas reinhardtii and Chlorella sp. in batch cultures was investigated in a novel gas-tight photobioreactor, in which CO2, H2, and N2 were titrated into the gas phase to control medium pH, dissolved oxygen partial pressure, and headspace pressure, respectively. The exit gas from the reactor was circulated through a loop of tubing and re-introduced into the culture. CO2 uptake was estimated from the addition of CO2 as acidic titrant and O2 evolution was estimated from titration by H2, which was used to reduce O2 over a Pd catalyst. The photosynthetic quotient, PQ, was estimated as the ratio between O2 evolution and CO2 up-take rates. NH4+, NO2−, or NO3− was the final cell density limiting nutrient. Cultures of both algae were, in general, characterised by a nitrogen sufficient growth phase followed by a nitrogen depleted phase in which starch was the major product. The estimated PQ values were dependent on the level of oxidation of the nitrogen source. The PQ was 1 with NH4+ as the nitrogen source and 1.3 when NO3− was the nitrogen source. In cultures grown on all nitrogen sources, the PQ value approached 1 when the nitrogen source was depleted and starch synthesis became dominant, to further increase towards 1.3 over a period of 3–4 days. This latter increase in PQ, which was indicative of production of reduced compounds like lipids, correlated with a simultaneous increase in the degree of reduction of the biomass. When using the titrations of CO2 and H2 into the reactor headspace to estimate the up-take of CO2, the production of O2, and the PQ, the rate of biomass production could be followed, the stoichiometrical composition of the produced algal biomass could be estimated, and different growth phases could be identified

A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ42 peptide (the 42-residue isoform of the amyloid-β peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant β-amyloid precursor protein (APP) lowered their brain levels of Aβ42. In cultured cells, the decrease in Aβ42 secretion was accompanied by an increase in the Aβ(1–38) isoform, indicating that NSAIDs subtly alter γ-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Aβ42 peptide levels independently of COX activity and that this Aβ42-lowering activity could be optimized to selectively target the pathogenic Aβ42 species

Land, history or modernization? Explaining ethnic fractionalization

Ethnic fractionalization (EF) is frequently used as an explanatory tool in models of economic development, civil war and public goods provision. However, if EF is endogenous to political and economic change, its utility for further research diminishes. This turns out not to be the case. This paper provides the first comprehensive model of EF as a dependent variable. It contributes new data on the founding date of the largest ethnic group in each state. It builds political and international variables into the analysis alongside historical and geoclimatic parameters. It extends previous work by testing models of politically relevant EF. In addition, this research interprets model results in light of competing theories of nationalism and political change. Results show that cross-national variation in EF is largely exogenous to modern politico-economic change. However, the data are inconclusive with respect to competing geoclimatic, historical institutional and modernist theories of ethnogenesis

The transition of reported pain in different body regions – a one-year follow-up study

BACKGROUND: The course of pain at a specific region such as the lower back has previously been shown as well as for generalized pain. However we have not found any report on the course of pain from various different specific regions. The aim of this investigation was to study the one-year transition of reported pain in different body locations. METHODS: From a general population 14555 men and women, 46–68 years, responded to an extensive health questionnaire including the standardized Nordic questionnaire. The population represented 27% of the total population within the age group in Malmö, Sweden. At the one year follow-up 12607 responded to the questionnaire, yielding a response rate of 87%. The one year prevalence of long-lasting pain and the pattern of pain reporting from different regions were studied for men and women. RESULTS: The one-year prevalence of long-lasting neck pain was 14% (95% CI 13–15) among men and 25% (95% CI 24–26) among women at baseline and 15% (95% CI 14–16) for the men and 23% (95% CI 22–24) for the women at follow-up. Of those reporting neck pain "all the time" at baseline, 48% of the men and 54% of the women also reported neck pain "all the time" at the one-year follow-up. At the follow-up neck pain was reported as present "often" by 43% of the men and 47% of the women who reported neck pain "often" at baseline. Similar transition pattern were found for neck, shoulders, elbow/wrist/hand and lower back symptoms, as well as consistent prevalence rates. CONCLUSION: The one-year transition pattern of reported pain was similar in different body regions and among men and women. Furthermore the prevalence rates of long-lasting pain in the population were consistent at baseline and the follow-up. The findings of similar transition patterns support the interpretation of long-lasting pain as a generalized phenomenon rather than attributed to specific exposure. This may have implications for future pain research

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa