Biomedical subjects

Jason L Eriksen

Publications and source records attributed to Jason L Eriksen.

5 recordsLinked to original sources

PubMed2003

Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity.

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of developing Alzheimer's disease. Recent evidence indicates that some NSAIDs specifically inhibit secretion of the amyloidogenic A beta 42 peptide in cultured cells and mouse models of Alzheimer's disease. The reduction of A beta 42 peptides is not mediated by inhibition of cyclooxygenases (COX) but the molecular mechanism underlying this novel activity of NSAIDs has not been further defined. We now demonstrate that NSAIDs efficiently reduce the intracellular pool of A beta 42 in cell-based studies and selectively decrease A beta 42 production in a cell-free assay of gamma-secretase activity. Moreover, we find that presenilin-1 (PS1) mutations, which affect gamma-secretase activity, differentially modulate the cellular A beta 42 response to NSAID treatment. Overexpression of the PS1-M146L mutation enhances the cellular drug response to A beta 42 lowering NSAIDs as compared with cells expressing wild-type PS1. In contrast, expression of the PS1-Delta Exon9 mutation strongly diminishes the A beta 42 response, showing that PS1 mutations can modulate the cellular drug response to NSAID treatment both positively and negatively. Enhancement of the NSAID drug response was also observed with overexpression of the APP V717F mutation but not with Swedish mutant APP, which affects beta-secretase cleavage. In sum, these results strongly suggest that NSAIDs represent a founding group of compounds that lower A beta 42 production by direct modulation of gamma-secretase activity or its substrate.

Amyloid Precursor Protein Secretases↗

PubMed2003

Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain.

Epidemiological studies indicate that long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) confers protection from Alzheimer's disease, and some NSAIDs were shown to specifically decrease production of the amyloidogenic Abeta42 peptide, most likely by direct modulation of gamma-secretase activity. In contrast to gamma-secretase inhibitors, Abeta42-lowering NSAIDs do not impair S3 cleavage in the NOTCH receptor and release of the NOTCH intracellular domain, a finding with conceptual implications for the development of safer drugs targeting Abeta production through gamma-secretase modulation. Intramembrane cleavage and release of an intracellular signaling domain has recently been demonstrated in a number of additional gamma-secretase substrates. We now show in cell-based assays that intramembrane cleavage of APP and ErbB-4 receptor is not impaired by the Abeta42-lowering NSAIDs, sulindac sulfide and ibuprofen. Generation of the APP intracellular domain (AICD) was further not inhibited in a cell-free assay at concentrations far exceeding those effective in reducing Abeta42 production. Closer inspection of AICD signaling showed that stabilization of the AICD peptide by FE65 and AICD-mediated transcription were also retained at Abeta42-lowering concentrations. These results demonstrate that S3-like/intramembrane cleavage is preserved by Abeta42-lowering NSAIDs in at least three substrates of gamma-secretase APP, ErbB-4, and NOTCH and underline the striking specificity by which these drugs target Abeta42 production.

Amino Acid Sequence↗

PubMed2003

Effects of ethanol and ipsapirone on the development of midline raphe glial cells and astrocytes.

Previously, results of studies from our laboratory have shown that the offspring of ethanol-fed female rats have a significant decrease in serotonin (5-HT) neurons and glia that contain S100B, an essential trophic factor for the development of 5-HT neurons. The deficiency of S100B-immunopositive glia was detected during the vulnerable period in 5-HT neuron development and in brain areas proximal to these neurons. The reductions of both 5-HT neurons and S100B-positive glia were prevented by maternal treatment with a 5-HT(1A) agonist (i.e., ipsapirone or buspirone). In the current study, we investigated whether the offspring of ethanol-fed rats had a general decrease in the density of glial cells in the brain areas that contain 5-HT neurons, and we determined whether these changes were prevented by maternal treatment with ipsapirone between gestational days (GDs) 13 and 20. We estimated the density of vimentin-positive glia of the midline raphe glial structure (MRGS) at GD 20 and postnatal day (PND) 5 and of glial fibrillary acidic protein (GFAP)-positive astrocytes proximal to the dorsal and median raphe at PNDs 5 and 19. The results of this study provide evidence that in utero ethanol exposure is associated with a reduced density of GFAP-immunopositive astrocytes proximal to the dorsal and median raphe. Maternal ipsapirone treatment significantly increased astroglial density in the dorsal raphe at PNDs 5 and 19 and in the median raphe at PND 5, such that it either prevented (dorsal raphe, PNDs 5 and 19) or blunted (median raphe, PND 5) the effects of ethanol.

Animals↗

PubMed2003

NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.

Alzheimer Disease↗

PubMed2002

Effects of ethanol and 5-HT1A agonists on astroglial S100B.

Previous studies from this and another laboratory demonstrated that in utero ethanol exposure reduces 5-HT neurons and S100B-immunopositive glia that are proximal to these neurons. Our laboratory also found that these effects are prevented by maternal treatment with a 5-HT(1A) agonist. Because of S100B's important role in the development of 5-HT neurons, the present study used both in vivo and in vitro models to investigate the potential involvement of S100B with the damaging effects of ethanol and with the protective effects of 5-HT(1A) agonists. We used in situ hybridization to address whether a 5-HT(1A) agonist could potentially affect S100B mRNA in vivo. Maternal treatment with buspirone between gestation days 13 and 20 significantly increased S100B mRNA in neuroepithelium of G20 offspring of control (40%) and ethanol-fed dams (20%). However, S100B mRNA was not altered in neuroepithelium from ethanol-exposed offspring. In astroglial cultures, we examined whether ethanol reduces the release of S100B and whether a 5-HT(1A) agonist could stimulate the release of this protein. We also evaluated the effects of ethanol and ipsapirone on astroglial content of S100B. Neither the concentration of S100B in astroglial media nor astroglial content of S100B were affected by ethanol. However, treatment with 100 nM ipsapirone, a 5-HT(1A) agonist, between the 6th and 7th day in vitro, increased astroglial release of S100B 2- to 3-fold. Thus, the protective effects of a 5-HT(1A) agonist on ethanol-treated 5-HT neurons might be associated with the ability of these drugs to release the neurotrophic factor S100B from astrocytes.

Alcohol-Induced Disorders, Nervous System↗