Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain

Dovey, Harry F.; John, Varghese; Anderson, John P.; Chen, L. Z.; Andrieu, P. D. S. int; Fang, Lanlan; Freedman, Stephen B.; Folmer, B.; Goldbach, Erich; Holsztynska, E. J.; Hu, Kang; Johnson-Wood, Kelly; Kennedy, S. L.; Kholodenko, Dora; Knops, Jeroen; Latimer, Lee H.; Lee, M.; Liao, Ziyuan; Lieberburg, Ivan; Motter, Ruth; Mutter, Linda; Nietz, J.; Quinn, Kevin P.; Sacchi, K. L.; Seubert, Peter; Shopp, George M.; Thorsett, Eugene D.; Tung, Jay S.; Wu, Jing; Yang, Shao Hua; Yin, Chen; Schenk, Dale; May, Patrick C.; Altstiel, Larry D.; Bender, Mark H.; Boggs, Leonard N.; Britton, T. C.; Clemens, James C.; Czilli, Dan L.; Dieckman-Mcginty, D. K.; Droste, J. J.; Fuson, Kimberly S.; Gitter, Bruce D.; Hyslop, Paul A.; Johnstone, Edward D.; Li, W.-Y.; Little, Sheila P.; Mabry, Thomas E.; Miller, Freeman D.; Ni, Binhui; Nissen, Jeffrey S.; Porter, Warren J.; Potts, B D; Reel, Jon K.; Stephenson, Diane; Su, Yuan; Shipley, Lisa A.; Whitesitt, Celia A.; Yin, Terry; Audia, James E.

doi:10.1046/j.1471-4159.2001.00012.x

Cited by 810 publications

(389 citation statements)

References 37 publications

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“…2-5 min after addition of RPMI the mixture was transferred into 5-10 mL of DMEM with 10% FBS, and seeded at ~50,000 per well on poly-D-Lysine-coated 96-well plates (BD Biosciences). After ~4 h the old media was aspirated and fresh media containing either DMSO, the γ-secretase inhibitor N-[N-(3,5-difluorophena cetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 μM) [32], or the γ-secretase inhibitor LY411575 (100 nM) [33] was added for overnight incubation.…”

Section: Methodsmentioning

confidence: 99%

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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The γ-secretase complex cleaves the carboxy-terminal 99 residue (C99) fragment of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. The catalytic activity of this complex is mediated either by the presenilin-1 (PS1) or the presenilin-2 (PS2) subunit. In vitro and in vivo studies have demonstrated that PS1-containing complexes generate more total Aβ product than PS2-containing complexes, indicating greater cleavage activity by PS1-containing γ-secretase complexes at the APP γ-site. However, it remains untested whether γ-secretase cleavage at the APP ε-site, which precedes γ-site cleavage and produces the physiologically active APP intracellular domain (AICD), follows the same rule. Using a novel Swedish APP-GVP substrate to facilitate the parallel detection of Aβ and AICD products from PS1-/-/PS2-/- cells co-transfected with either PS1 or PS2, we observed that while PS1 generates more total Aβ product than PS2, consistent with published reports, PS1 and PS2 unexpectedly generate equal amounts of AICD product. We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain (NICD), indicating equal cleavage activity at the Notch S3-site (the corollary of the APP ε-site). Our findings suggest that processivity differences between PS1 and PS2 underlie the differential production of Aβ peptide. Taken together these findings offer novel insights into γ-secretase biology and have important implications for therapeutically targeting γ-secretase

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Section: Methodsmentioning

confidence: 99%

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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“…To define the role of Notch signaling during ectoderm specification, we inhibited Notch signaling with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, during ectoderm specification of hESCs (Dovey et al, 2001). In the presence of DAPT Notch signaling was inhibited, as indicated by the lack of NICD expression during differentiation (Fig.…”

Section: Inactivation Of Notch Signaling Promotes P63 Expression In Dmentioning

confidence: 99%

Notch signaling represses p63 expression in the developing surface ectoderm

Tadeu

Horsley

2013

Development

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MiceK14-H2BGFP transgenic mice (Tumbar et al., 2004) SUMMARYThe development of the mature epidermis requires a coordinated sequence of signaling events and transcriptional changes to specify surface ectodermal progenitor cells to the keratinocyte lineage. The initial events that specify epidermal keratinocytes from ectodermal progenitor cells are not well understood. Here, we use both developing mouse embryos and human embryonic stem cells (hESCs) to explore the mechanisms that direct keratinocyte fate from ectodermal progenitor cells. We show that both hESCs and murine embryos express p63 before keratin 14. Furthermore, we find that Notch signaling is activated before p63 expression in ectodermal progenitor cells. Inhibition of Notch signaling pharmacologically or genetically reveals a negative regulatory role for Notch signaling in p63 expression during ectodermal specification in hESCs or mouse embryos, respectively. Taken together, these data reveal a role for Notch signaling in the molecular control of ectodermal progenitor cell specification to the epidermal keratinocyte lineage.

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“…To test if this is a plausible mechanism for p53 induction in activated T cells, we first modulated cMyc expression through the indirect inhibition of Notch by DAPT, a g-secretase inhibitor. 37,24 Treatment with DAPT lowered cMyc levels and proliferation of activated T cells. 23 The cMyc target p14ARF was also downregulated in these cells.…”

Section: Discussionmentioning

confidence: 99%

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

et al. 2016

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Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells.

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Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain

Cited by 810 publications

References 37 publications

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Notch signaling represses p63 expression in the developing surface ectoderm

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

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