Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Basi, Guriqbal S.; Hemphill, Susanna S.; Brigham, Elizabeth F.; Liao, Anna; Aubele, Danielle L.; Baker, Jeanne; Barbour, Robin; Bova, Michael P.; Chen, Xiaohua; Dappen, Michael S.; Eichenbaum, Tovah; Goldbach, Erich; Hawkinson, Jon E.; Lawler-Herbold, Rose; Hu, Kang; Hui, Terence; Jagodziński, Jacek; Keim, Pamela S.; Kholodenko, Dora; Latimer, Lee H.; Lee, Mike; Marugg, Jennifer L.; Mattson, Matthew N.; McCauley, Scott; Miller, James L.; Motter, Ruth; Mutter, Linda; Neitzel, Martin L.; Ni, Huifang; Nguyen, Lan K.; Quinn, Kevin P.; Ruslim, Lany; Semko, Christopher M.; Shapiro, Paul; Smith, Jenifer; Soriano, Ferdie; Szőke, Balázs; Tanaka, Kevin; Tang, Pearl; Tucker, John; Ye, Xiacong Michael; Yu, Mei; Wu, Jing; Xu, Yinchuan; Garofalo, Albert W.; Sauer, John Michael; Konradi, Andrei W.; Ness, Daniel; Shopp, George M.; Pleiss, Michael A.; Freedman, Stephen B.; Schenk, Dale

doi:10.1186/alzrt60

Cited by 41 publications

(35 citation statements)

References 98 publications

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“…The binding of azepine and sulfonamide GSIs with an allosteric site on PS, rather than the catalytic site, raises the possibility of differential inhibitory interactions as PS processes different substrates, such as APP and Notch. Consistent with this hypothesis, in vitro studies have shown varying substrate differentiation for GSIs in the allosteric class, but not for GSIs in the isostere class (Lewis et al, 2003;Kreft et al, 2008;Olson and Albright, 2008;Martone et al, 2009;Basi et al, 2010;Chávez-Guttiérez et al, 2012;Mitani et al, 2012). One GSI, LY-411575, was shown to reduce Ab40 and Ab42 levels in plasma and in the brains of CRND8 transgenic mice while causing intestinal goblet metaplasia and thymic atrophy (Wong et al, 2004).…”

Section: Discussionmentioning

confidence: 54%

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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Section: Discussionmentioning

confidence: 54%

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

Albright

Dockens

Meredith

et al. 2012

J Pharmacol Exp Ther

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“…To verify this finding, we next used the amino- and carboxy-terminally truncated NotchΔEΔC-HA substrate [31], which incorporates a c-terminal HA-epitope tag to facilitate NICD detection by ELISA (Fig. 2C ).…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, the ectodomain of Swedish APP695 was PCR amplified and blunt-end ligated in-frame into linearized APP C99-GVP using the In-Fusion PCR Cloning System (Clontech). Swedish APP695, NotchΔE, NotchΔEΔC, Human PS1, and Human PS2 cDNA constructs were previously described [29-31]. …”

Section: Methodsmentioning

confidence: 99%

“…Aβ1-x was quantified using antibody 266 (epitope Aβ16-23) for capture and biotinylated antibody 2H3 (epitope Aβ4-7) for detection, and both antibodies have been described previously [28]. NICD was quantified using antibody 9F3 (N-terminal neo-epitope, [31]) for capture and a biotinylated anti-HA antibody for detection. For AICD and NICD ELISAs, cell lysates were harvested in 1X Passive Lysis Buffer, plates were briefly centrifuged to pellet debris, and recovered lysate was added to each well of the appropriate ELISA plate.…”

Section: Methodsmentioning

confidence: 99%

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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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“…Therefore, nontransgenic mice are currently in use for testing the GSI efficacy of A␤ lowering (Basi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors

Lu¹,

Zhang²,

Nolan³

et al. 2011

J Pharmacol Exp Ther

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Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of ␤-or ␥-secretase, key enzymes for the production of amyloid ␤ (A␤), may be viable mechanisms for the treatment of AD. For the discovery of ␥-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of A␤ species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for A␤ lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF A␤ across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain A␤x-42 and CSF A␤x-40 in the 129/SVE mouse is indicative of that for human CSF A␤. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of A␤ data are established.

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Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

Cited by 41 publications

References 98 publications

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

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

Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors

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