Selective inhibition of Aβ42 production by NSAID <i>R</i>‐enantiomers

Morita, Takashi; Chu, Teresa; Ubeda, Oliver J.; Beech, Walter; Cole, Gregory M.

doi:10.1046/j.1471-4159.2002.01195.x

Cited by 142 publications

(135 citation statements)

References 21 publications

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“…The results are also in line with previous clinical evidence showing that CHF5074 administration reduces TNFa levels in cerebrospinal fluid of healthy subjects and of MCI patients (Ross et al, 2013). Worth of note, the peculiar modulation of M2 microglial transcription by CHF5074 in primary cultures was not reproduced by the classical NSAID ibuprofen or by the atypical NSAID R-flurbiprofen devoid of cyclooxygenase inhibitory activity (Morihara et al, 2002). In line with previous evidence (Ogawa et al, 2000;Hinz et al, 2000;Heneka et al, 2005), either ibuprofen or R-flurbiprofen diminished iNOS mRNA, but neither compound modified MRC1 or TREM2 expression.…”

Section: Discussionsupporting

confidence: 83%

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

et al. 2015

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Abstract-Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1b), Tumor Necrosis Factor alpha (TNFa) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/ phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-a, IL-1b and iNOS induced by 10 lM b-amyloid 1-42 (Ab 42 ). Moreover, CHF5074 significantly increased the expression of antiinflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Ab 42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 lM or 500 lM) or R-flurbiprofen (3 lM or 100 lM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.

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Section: Discussionsupporting

confidence: 83%

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

et al. 2015

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“…Considering the first of these three mechanisms, high dose ibuprofen (100-500 mM) has been shown to reduce Ab42 production in vitro, an effect also shown by other NSAIDs to be independent of their antiinflammatory effects on regulating COX, PPAR, and NFkB (Weggen et al, 2001;Morihara et al, 2002;Sagi et al, 2003;Takahashi et al, 2003). Although the COX-dependency of ibuprofen's effects on Ab42 suppression has not been tested, another NSAID sulindac has been more extensively analyzed and clearly reduces Ab42 independent of COX (Weggen et al, 2001;Sagi et al, 2003;Takahashi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The human ACT gene has enhancer elements responsive to IL-1-bstimulated NFkB and AP-1 (Kordula et al, 2000) and human ACT mRNA expression is directly controlled by NFkB (Lieb et al, 1996). As ibuprofen is a weak NFkB inhibitor (Tegeder et al, 2001), it is possible that higher levels of ibuprofen or the less toxic R-flurbiprofen (Morihara et al, 2002) could directly reduce human ACT expression levels by inhibiting NFkB.…”

Section: Discussionmentioning

confidence: 99%

“…The major inflammatory target of NSAIDs, including ibuprofen, is cyclooxygenase (COX), and in our model ibuprofen-induced plaque reduction was associated with reductions in brain interleukin-1b, a downstream target of COX. Although this and other evidence suggests a possible role of inflammation in controlling plaque pathogenesis, this hypothesis has been challenged by discovery of an unexpected COX-independent function of a subset of NSAIDs (including ibuprofen) in reducing Ab42 production in vitro (Weggen et al, 2001(Weggen et al, , 2003aMorihara et al, 2002;Eriksen et al, 2003;Sagi et al, 2003;Takahashi et al, 2003;Zhou et al, 2003). Adding to the controversy whether the mechanism(s) of plaque reduction are inflammationdependent or -independent, it is unclear whether the high ibuprofen concentrations required in vitro to reduce Ab42 production can be attained in the human brain with doses shown epidemiologically to reduce AD risk.…”

Section: Introductionmentioning

confidence: 99%

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Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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“…Contrary to these traditional views, however, it has recently been shown that a subset of NSAIDs (ibuprofen, sulindac sulfide (SSide), indomethacin, and R-flurbiprofen) selectively decrease the secretion of A␤42 from cultured cells independently of COX activity and lowers the amount of soluble A␤42 in the brains of transgenic mice (21,22). In cultured cells, the decrease in A␤42 secretion caused by SSide was accompanied by an increase in A␤38 generation, whereas the Notch site-3 cleavage activity to generate Notch intracellular domain (NICD) was not significantly affected.…”

mentioning

confidence: 99%

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

Takahashi

Hayashi

Tominari

et al. 2003

Journal of Biological Chemistry

184

189

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic A␤42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of ␥-secretase for A␤42 generation (␥ 42 -secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on ␥-secretase and preferentially inhibits the ␥ 42 -secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro ␥-secretase assay using recombinant amyloid ␤ precursor protein C100 as a substrate. SSide also inhibits activities for the generation of A␤40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for ␥ 42 -secretase in vitro. Our data suggest that SSide is a direct inhibitor of ␥-secretase that preferentially affects the ␥ 42 -secretase activity. Alzheimer's disease (AD)1 is a dementing neurodegenerative disorder of the elderly characterized pathologically by neuronal loss in the cerebral cortex accompanied by massive deposition of amyloid ␤ peptides (A␤) as senile plaques (1). A␤ is produced by sequential proteolytic cleavages of the amyloid ␤ precursor protein (␤APP) by a set of membrane-bound proteases termed ␤-and ␥-secretases. The C-terminal length of A␤ generated by ␥-secretase is heterogeneous; A␤42 is a relatively minor molecular species of the A␤ secreted from cells, but it has a much higher propensity to aggregate and form amyloid compared with other A␤ species. These findings provide strong support for the hypothesis that the deposition of A␤42 is closely related to the pathogenesis of AD, implicating ␥-secretase as an important therapeutic target.Mutations in PS1 or PS2 genes account for the majority of early onset familial AD, and these mutations cause an increase in the ratio or levels of production of A␤42 (1). It is known that PS is essential for the ␥-secretase-mediated intramembranous cleavage not only for ␤APP but for other type I transmembrane proteins (e.g. Notch, ErbB4, E-cadherin, low density lipoprotein receptor-related protein, and CD44) (2). PS proteins undergo endoproteolysis to generate N-and C-terminal fragments and interact with other proteins (i.e. nicastrin, APH-1, and PEN-2) to form a high molecular weight (HMW) protein complex (3). The functional role of PS complex in ␥-secretase activity still remains unknown. However, aspartyl protease transition state analogue inhibitors of ␥-secretase, which harbors a hydroxyl ethylene isostere or a difluoro alcohol moiety, directly label PS fragments (4 -6). In addition, a systematic analysis using a variety of PS mutants revealed that HMW complex formation of PS as well as conserved aspartyl residues within the transmembrane domain are es...

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Selective inhibition of Aβ42 production by NSAID R‐enantiomers

Cited by 142 publications

References 21 publications

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation

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