γ‐secretase inhibitors for the treatment of Alzheimer's disease

Wu, Wen‐Lian; Zhang, Lili

doi:10.1002/ddr.20288

Cited by 28 publications

(17 citation statements)

References 64 publications

(54 reference statements)

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“…Long-term treatment with high doses of DAPT causes damage to organs, including intestine and kidney, which could limit the potential clinical use of this class of reagents (33). Our DAPT regimen did not affect liver, lung, small intestine, or kidney at the microscopic level, nor did it affect body weight or survival (Supplemental Figure 7 and data not shown).…”

Section: Long-term Notch Inhibition By Dapt Prevents Bone Loss In Tnfmentioning

confidence: 90%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss. IntroductionPatients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), often have severe systemic bone loss and increased risk of fracture due to increased bone resorption and decreased bone formation, partially mediated by elevated TNF levels (1). We (1-4) and others (5, 6) have reported that TNF inhibits bone formation by affecting major osteoblast regulatory pathways, including BMP/SMAD/RUNX2 and WNT-β-catenin, but the role of TNF in osteoblast differentiation from MSCs has not been fully defined. The TNF transgenic (TNF-Tg) mouse model we use, line 3647, represents a good model of RA to study the influence of chronically elevated, but relatively low, levels of TNF and TNF-induced inflammation on bone cell function and MSC differentiation into osteoblasts (7). To attempt to identify molecules responsible for reduced differentiation of MSCs into osteoblasts in RA, we performed genome-wide screening and pathway analyses using data from RNA sequencing (RNA-Seq) of MSCs purified from TNF-Tg mice and WT littermates. We found that genes in the NOTCH and noncanonical NF-κB signaling pathways were markedly upregulated in TNF-Tg mouse MSCs, raising the possibility that NOTCH may interact with noncanonical NF-κB proteins in MSCs to inhibit their osteogenic differentiation.NOTCH is a family of evolutionarily conserved receptors that regulate cell fate. NOTCH receptors are activated following direct contact with their ligands expressed on adjacent cells. In mammals, there are 4 NOTCH receptors (NOTCH1-NOTCH4)...

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Section: Long-term Notch Inhibition By Dapt Prevents Bone Loss In Tnfmentioning

confidence: 90%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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“…Several potent, small-molecule GSIs have been developed (Olson and Albright, 2008;Wu and Zhang, 2009). Structurefunction studies have shown that GSIs selected for in vivo use, the azepines and sulfonamides, bind a common allosteric inhibitory site on presenilin (PS), rather than the site targeted by GSIs in the isostere class and are believed to interact with the active site of the enzyme (Olson and Albright, 2008;Steiner et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

Albright

Dockens

Meredith

et al. 2012

J Pharmacol Exp Ther

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A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid b-peptide (Ab), generated by g-secretasemediated cleavage of the amyloid precursor protein (APP). Therefore, g-secretase inhibitors (GSIs) may lower brain Ab and offer a potential new approach to treat AD. As g-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Ab and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Ab levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notchregulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Ab40 and Ab42 levels similarly. Chronic administration in rats and dogs, and 28-day, single-and multipleascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Ab40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Ab levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

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“…␥-Secretase activity is required for signaling by the Notch-family of transmembrane receptors. Inhibition of Notch signaling could cause gastrointestinal toxicity and mechanism-based side effects [9,10]. Therefore, the selectivity for inhibition is critical for the drug efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%