1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

Imbimbo, Bruno P.; Giudice, Elda Del; Colavito, Davide; D’Arrigo, Antonello; Carbonare, Maurizio Dalle; Villetti, Gino; Facchinetti, Fabrizio; Volta, Roberta; Pietrini, Vladimiro; Baroc, M. F.; Serneels, Lutgarde; Strooper, Bart De; Leon, Alberta

doi:10.1124/jpet.107.129007

Cited by 82 publications

(92 citation statements)

References 41 publications

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“…In this report, we describe a novel piperidine-based ␥ -secretase modulator, GSM-10h [14] , which is more potent than the previously described NSAID derivatives [7][8][9][10][11] and displays the profile of a ␥ -secretase modulator in vitro and in vivo. In SH-SY5Y-APPswe cells, GSM-10h reduced the level of A ␤ 42 whilst having no effect on the level of A ␤ 40 .…”

Section: Discussionmentioning

confidence: 99%

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

Hussain

Harrison²,

Hawkins³

et al. 2010

Neurodegener Dis

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Background: Cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aβ₄₂ peptide while avoiding deleterious activity on Notch processing. Objective: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aβ peptides to induce neurotoxicity in rat primary cortical neurons. Methods: The effect of GSM-10h on Aβ levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. Results:In cells, GSM-10h decreased levels of Aβ₄₂ while concomitantly increasing levels of Aβ₃₈ in the absence of effects on Aβ₄₀ levels. In TASTPM mice, GSM-10h effectively lowered brain Aβ₄₂ and increased brain Aβ₃₈, with no effect on Notch signalling. Unlike Aβ₄₂, which causes neuronal cell death, neither Aβ₃₇ nor Aβ₃₈ were neurotoxic. Conclusions: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.

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Section: Discussionmentioning

confidence: 99%

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

Hussain

Harrison²,

Hawkins³

et al. 2010

Neurodegener Dis

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“…GSMs such as sulindac sulfide and ibuprofen were first discovered in the class of nonsteroidal anti-inflammatory drugs (7), and recent derivatives have shown promise as therapeutic agents in AD animal models and clinical trials (9,10). Several characteristics indicate that GSMs act directly on the ␥-secretase complex or its substrate APP, including their activity in cell-free ␥-secretase assays (4 -6, 11, 12), their ability to affect conformation of presenilin-1 (PS1) (13), and the observation that overexpression of FAD PS1 mutations altered the cellular response to GSMs, resulting in enhanced or diminished A␤42 reductions (12,14).…”

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confidence: 99%

Independent Generation of Aβ42 and Aβ38 Peptide Species by γ-Secretase

Czirr

Cottrell

Leuchtenberger

et al. 2008

Journal of Biological Chemistry

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Proteolytic processing of the amyloid precursor protein by ␤-and ␥-secretase generates the amyloid-␤ (A␤) peptides, which are principal drug targets in Alzheimer disease therapeutics. ␥-Secretase has imprecise cleavage specificity and generates the most abundant A␤40 and A␤42 species together with longer and shorter peptides such as A␤38. Several mechanisms could explain the production of multiple A␤ peptides by ␥-secretase, including sequential processing of longer into shorter A␤ peptides. A novel class of ␥-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower A␤42 levels without a change in A␤40 levels. A signature of GSMs is the concomitant increase in shorter A␤ peptides, such as A␤38, leading to the suggestion that generation of A␤42 and A␤38 peptide species by ␥-secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished A␤42 reductions as compared with wild type PS1. We have now used this model system to investigate whether A␤38 production would be similarly affected indicating coupled generation of A␤42 and A␤38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased A␤38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other A␤ peptide species. These data provide evidence that A␤42 and A␤38 species can be independently generated by ␥-secretase and argue against a precursor-product relationship between these peptides.A variety of therapeutic strategies in clinical development for Alzheimer disease (AD), 2 the most common neurodegenerative disorder, target the amyloid-␤ (A␤) peptides that are generated through proteolytic processing of the transmembrane amyloid precursor protein (APP) (1). In the A␤-producing pathway, APP is cleaved by two aspartyl proteases, first by ␤-secretase within its ectodomain and subsequently by ␥-secretase, which cleaves APP within its transmembrane domain (TMD) (2). ␥-Secretase is a multiprotein complex with the presenilin (PS) proteins at its enzymatic core (2). Because of its imprecise cleavage specificity, ␥-secretase generates A␤ peptides of variable length at the carboxyl terminus, with the highly amyloidogenic A␤42 isoform thought to be the key pathogenic species (3). A central role of A␤42 developed largely from genetic research demonstrating that mutations in the APP and PS genes associated with early-onset familial AD (FAD) invariably increase the A␤42/A␤40 ratio in primary fibroblast...

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“…The term selective amyloid lowering agents (SALA) was coined for this 'new' drug class, represented by R-flurbiprofen (tarenflurbil), a drug that provided positive phase 2 clinical trial data in AD patients before failing in a phase 3 trial (Wilcock et al 2008). Changes in the levels of Ab by NSAID SALAs in vitro and in vivo has been widely explained by modulation of Ab production (Weggen et al 2001;Eriksen et al 2003;Narlawar et al 2006;Imbimbo et al 2007b;Stock et al 2006;Peretto et al 2005). A number of mechanisms have been proposed, including the direct modulation of c-secretase activity (Weggen et al 2001;Eriksen et al 2003), downregulation of b secretase (Sastre et al 2003(Sastre et al , 2006, and Rho inhibition (Zhou et al 2003).…”

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Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

Abdul-Hay

Edirisinghe

Thatcher

2009

Journal of Neurochemistry

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Gamma‐secretase modulators (GSMs) include selected non‐steroidal anti‐inflammatory drugs such as flurbiprofen that selectively lowers the neurotoxic amyloid‐β peptide Aβ1–42. GSMs are attractive targets for Alzheimer’s disease, in contrast to ‘inverse GSMs,’ such as fenofibrate, which selectively increase the level of Aβ1–42. A methodology for screening of Aβ modulating drugs was developed utilizing an Aβ‐producing neuroblastoma cell line stably transfected with mutant human amyloid precursor protein, immunoprecipitation of Aβ peptides, and mass spectroscopic quantitation of Aβ1–37/Aβ1–38/Aβ1–40/Aβ1–42 using an Aβ internal standard. The unexpected conclusion of this work was that in this system, drug effects are independent of γ‐secretase. The methodology recapitulated reported results for modulation of Aβ by GSMs. However, control experiments in which exogenous Aβ1–40/Aβ1–42 was added (i) to drug‐treated wild‐type cells or (ii) to conditioned media from these wild‐type cells, gave comparable patterns of Aβ modulation. These results, suggesting that drugs modulate the ability of cell‐derived factors to degrade Aβ, was interrogated by adding protease inhibitors and performing molecular weight cut‐off fractionation. The results confirmed that modulation of Aβ1–40/Aβ1–42 was mediated by selective proteolysis. Treatment of N2a cells with flurbiprofen or fenofibric acid selectively enhanced Aβ1–42 clearance by extracellular proteolysis; treatment with HCT‐1026 or fenofibrate (esters of flurbiprofen and fenobric acid) inhibited clearance of Aβ1–40 and Aβ1–42.

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1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

Cited by 82 publications

References 41 publications

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

Independent Generation of Aβ42 and Aβ38 Peptide Species by γ-Secretase

Selective modulation of amyloid‐β peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Aβ levels

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