P2‐338: Substrate‐targeting gamma‐secretase modulators

Kukar, Thomas; Ladd, Thomas B.; Bann, Maralyssa; Fraering, Patrick C.; Maharvi, Ghulam M.; Moore, Brenda D.; Rangachari, Vijayaraghavan; Welzel, Alfred T.; Ye, Wenjuan; Sagi, Sarah A.; Cottrell, Barbara A.; Torpey, Justin W.; Rosenberry, Terrone L.; Fauq, Abdul H.; Wolfe, Michael S.; Schmidt, Boris; Walsh, Dominic M.; Koo, Edward H.; Golde, Todd E.

doi:10.1016/j.jalz.2008.05.1415

Cited by 56 publications

(86 citation statements)

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“…then, interaction of NCt with other proteins, such as OCIaD2, might increase the substrate selectivity of NCt toward aPP. In addition, substrate selectivity of γ-secretase could also be regulated by substrate selective γ-secretase modulator which interacts with aPP [20]. In this context, OCIaD2 enhanced the interaction of NCt with C99 but not with Notch, and was able to interact with C99 but not with Notch.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, only GPR3 and β-arrestin1 exhibit Notch-sparing activity without sharing a common mechanism of action. In addition, a small molecule has been identified that can also regulate aPP processing by binding to aPP, leading to the generation of a nontoxic form of aβ without causing the side effects associated with Notch deficiency [20]. these results raise the possibility that γ-secretase components, and/or substrate-targeting γ-secretase modulators, are involved.…”

Section: Introductionmentioning

confidence: 99%

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OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

Han

Jung

Jang

et al. 2013

Cell. Mol. Life Sci.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

Han

Jung

Jang

et al. 2013

Cell. Mol. Life Sci.

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“…A subset of non-steroidal antiinflammatory drugs (NSAIDs) were the first Notch-sparing small molecules shown to selectively lower Ab42 and subsequently raise Ab38 both in vitro and in vivo 19,20 . These g-secretase modulators (GSMs) were initially shown to bind to APP, although some more recent studies demonstrated that they also can target g-secretase 21,22 . Although the precise molecular mechanism of action remains poorly understood, a number of these molecules have advanced to clinical trials 23 .…”

mentioning

confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical g-secretase modulators affect the processing of APP by the g-secretase complex and the production of the amyloid-beta peptide Ab42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both g-and e-cleavage sites, by raising the Ab42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to g-secretase modulators, which shift Ab42 production towards the shorter Ab38, but unequivocally spare the e-site and APP-and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its g-site, modifying at the same time, the solvation of the e-site.

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“…Other reports assume that GSMs can interact with cellular membranes and alter biophysical properties of the lipid bilayer (11)(12)(13). Evidence was also provided that GSMs target the enzyme's substrate when GSM photoprobes labeled APP (14). However, recent NMR results have questioned specific APP binding sites of GSMs (15).…”

mentioning

confidence: 99%

Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization

Richter

Munter

Neß

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

101

151

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Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by γ-secretase result in the release of amyloid-β (Aβ) peptides of variable length. Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer's disease, as they are believed to initiate neuronal degeneration. Sulindac sulfide, which is known as a potent γ-secretase modulator (GSM), selectively reduces Aβ42 production in favor of shorter Aβ species, such as Aβ38. By studying APP-TMS dimerization we previously showed that an attenuated interaction similarly decreased Aβ42 levels and concomitantly increased Aβ38 levels. However, the precise molecular mechanism by which GSMs modulate Aβ production is still unclear. In this study, using a reporter gene-based dimerization assay, we found that APP-TMS dimers are destabilized by sulindac sulfide and related Aβ42-lowering compounds in a concentration-dependent manner. By surface plasmon resonance analysis and NMR spectroscopy, we show that sulindac sulfide and novel sulindac-derived compounds directly bind to the Aβ sequence. Strikingly, the attenuated APP-TMS interaction by GSMs correlated strongly with Aβ42-lowering activity and binding strength to the Aβ sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP-TMS. We conclude that these GSMs decrease Aβ42 levels by modulating APP-TMS interactions. This effect specifically emphasizes the importance of the dimeric APP-TMS as a promising drug target in Alzheimer's disease.

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P2‐338: Substrate‐targeting gamma‐secretase modulators

Cited by 56 publications

References 0 publications

OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization

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