Sequential processing of the β-amyloid precursor protein by β- and γ-secretase generates the amyloid β-peptide (Aβ), which is widely believed to play a causative role in Alzheimer disease. Selective lowering of the pathogenic 42-amino acid variant of Aβ by γ-secretase modulators (GSMs) is a promising therapeutic strategy. Here we report that mutations in presenilin (PS), the catalytic subunit of γ-secretase, display differential responses to non-steroidal anti-inflammatory drug (NSAID)-type GSMs and more potent second-generation compounds. Although many pathogenic PS mutations resisted lowering of Aβ42 generation by the NSAID sulindac sulfide, the potent NSAID-like second-generation compound GSM-1 was capable of lowering Aβ42 for many but not all mutants. We further found that mutations at homologous positions in PS1 and PS2 can elicit differential Aβ42 responses to GSM-1, suggesting that a positive GSM-1 response depends on the spatial environment in γ-secretase. The aggressive pathogenic PS1 L166P mutation was one of the few pathogenic mutations that resisted GSM-1, and Leu-166 was identified as a critical residue with respect to the Aβ42-lowering response of GSM-1. Finally, we found that GSM-1-responsive and -resistant PS mutants behave very similarly toward other potent second-generation compounds of different structural classes than GSM-1. Taken together, our data show that a positive Aβ42 response for PS mutants depends both on the particular mutation and the GSM used and that attenuated Aβ42 responses to low potency GSMs can be overcome for many PS mutants by second generation GSMs. Sequential processing of the β-amyloid precursor protein by β- and γ-secretase generates the amyloid β-peptide (Aβ), which is widely believed to play a causative role in Alzheimer disease. Selective lowering of the pathogenic 42-amino acid variant of Aβ by γ-secretase modulators (GSMs) is a promising therapeutic strategy. Here we report that mutations in presenilin (PS), the catalytic subunit of γ-secretase, display differential responses to non-steroidal anti-inflammatory drug (NSAID)-type GSMs and more potent second-generation compounds. Although many pathogenic PS mutations resisted lowering of Aβ42 generation by the NSAID sulindac sulfide, the potent NSAID-like second-generation compound GSM-1 was capable of lowering Aβ42 for many but not all mutants. We further found that mutations at homologous positions in PS1 and PS2 can elicit differential Aβ42 responses to GSM-1, suggesting that a positive GSM-1 response depends on the spatial environment in γ-secretase. The aggressive pathogenic PS1 L166P mutation was one of the few pathogenic mutations that resisted GSM-1, and Leu-166 was identified as a critical residue with respect to the Aβ42-lowering response of GSM-1. Finally, we found that GSM-1-responsive and -resistant PS mutants behave very similarly toward other potent second-generation compounds of different structural classes than GSM-1. Taken together, our data show that a positive Aβ42 response for PS mutants depends both on the particular mutation and the GSM used and that attenuated Aβ42 responses to low potency GSMs can be overcome for many PS mutants by second generation GSMs. IntroductionThe amyloid β-peptide (Aβ) 4The abbreviations used are: Aβamyloid β-peptideADAlzheimer diseaseAPPβ-amyloid precursor proteinFADfamilial Alzheimer diseaseGSMγ-secretase modulatorNSAIDnon-steroidal anti-inflammatory drugPSpresenilinTMDtransmembrane domainTris-BicineTris-N,N-bis(2-hydroxyethyl)glycine. is a 37–43-amino acid secreted peptide and an invariant pathological hallmark of Alzheimer disease (AD). The 42-amino acid variant Aβ42 has been suggested to be causative for the disease by triggering the amyloid cascade, a sequence of pathogenic events that ultimately leads to neurodegeneration and dementia in affected patients (1Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (10796) Google Scholar). The pathogenic peptide is generated by a sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretase (2Haass C. EMBO J. 2004; 23: 483-488Crossref PubMed Scopus (479) Google Scholar). After β-secretase cleavage, γ-secretase cleaves the C-terminal fragment of APP that is left in the membrane by an intramembrane cleavage to release the various Aβ species (3Steiner H. Fluhrer R. Haass C. J. Biol. Chem. 2008; 283: 29627-29631Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 4Tolia A. De Strooper B. Semin. Cell Dev. Biol. 2009; 20: 211-218Crossref PubMed Scopus (75) Google Scholar, 5Wolfe M.S. Semin. Cell Dev. Biol. 2009; 20: 219-224Crossref PubMed Scopus (73) Google Scholar). Although Aβ42 is normally a minor species produced by this cleavage besides the major Aβ40 species, its production is enhanced by familial AD (FAD) mutations in presenilin (PS) 1 and PS2, the catalytic component of γ-secretase (6Steiner H. Curr. Alzheimer Res. 2008; 5: 147-157Crossref PubMed Scopus (34) Google Scholar), as well as by a subset of FAD mutations in APP. Targeting β- and γ-secretase by specific inhibitors is one of the current approaches toward an effective AD treatment (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar). With respect to γ-secretase, however, γ-secretase inhibitors also block the cleavage of Notch1, a major physiological γ-secretase substrate and, thus, the generation of the Notch1 intracellular domain (NICD), which is a crucial signaling molecule controlling cell differentiation (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar). Interfering with the cleavage of this substrate accounts for adverse side effects in animal studies (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar) and probably in humans as well. γ-Secretase modulators (GSMs) that selectively lower Aβ42, such as a subset of non-steroidal anti-inflammatory drugs (NSAIDs), are considered to be a safer approach than using inhibitors of γ-secretase that target the active site of the protease. These compounds lower Aβ42 generation without affecting Notch1 intracellular domain generation, thus precluding potential Notch-related side effects (8Weggen S. Eriksen J.L. Das P. Sagi S.A. Wang R. Pietrzik C.U. Findlay K.A. Smith T.E. Murphy M.P. Bulter T. Kang D.E. Marquez-Sterling N. Golde T.E. Koo E.H. Nature. 2001; 414: 212-216Crossref PubMed Scopus (1317) Google Scholar). More potent drugs than NSAIDs, such as the NSAID-like GSM-1 and others effective in the nanomolar range, have been recently identified (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar).The precise mechanistic mode(s) of action as well as the binding site(s) of GSMs, being on the substrate, the enzyme, and/or both, has not yet been fully resolved and may also differ for various types of GSMs (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 11Kukar T.L. Ladd T.B. Bann M.A. Fraering P.C. Narlawar R. Maharvi G.M. Healy B. Chapman R. Welzel A.T. Price R.W. Moore B. Rangachari V. Cusack B. Eriksen J. Jansen-West K. Verbeeck C. Yager D. Eckman C. Ye W. Sagi S. Cottrell B.A. Torpey J. Rosenberry T.L. Fauq A. Wolfe M.S. Schmidt B. Walsh D.M. Koo E.H. Golde T.E. Nature. 2008; 453: 925-929Crossref PubMed Scopus (271) Google Scholar). Many GSMs typically shift the cleavage specificity of γ-secretase such that the inhibition of Aβ42 generation is accompanied by an generation of the (8Weggen S. Eriksen J.L. Das P. Sagi S.A. Wang R. Pietrzik C.U. Findlay K.A. Smith T.E. Murphy M.P. Bulter T. Kang D.E. Marquez-Sterling N. Golde T.E. Koo E.H. Nature. 2001; 414: 212-216Crossref PubMed Scopus (1317) Google Scholar). GSMs, such as the NSAID an of and the and species is J.L. Sagi S.A. Smith T.E. S. Das P. Koo E.H. Golde T.E. J. PubMed Scopus Google Scholar). to Aβ42, the by and also the and Aβ40 as well as the species can be by GSMs, suggesting a of GSM action R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). modulators have also been identified that the Aβ42 species lowering the species T. Murphy M.P. Eriksen J.L. Sagi S.A. S. Smith T.E. Ladd T. M.A. R. J. M. S. Das P. Fauq A. Koo E.H. Golde T.E. PubMed Scopus Google Scholar). GSMs to target the substrate by binding to a of the Aβ domain in the of the APP domain T.L. Ladd T.B. Bann M.A. Fraering P.C. Narlawar R. Maharvi G.M. Healy B. Chapman R. Welzel A.T. Price R.W. Moore B. Rangachari V. Cusack B. Eriksen J. Jansen-West K. Verbeeck C. Yager D. Eckman C. Ye W. Sagi S. Cottrell B.A. Torpey J. Rosenberry T.L. Fauq A. Wolfe M.S. Schmidt B. Walsh D.M. Koo E.H. Golde T.E. Nature. 2008; 453: 925-929Crossref PubMed Scopus (271) Google Scholar). More the binding of GSMs to Aβ has been to of the APP lowering Aβ42 generation P. A. D. C. R. M. D. G. EMBO J. PubMed Scopus Google Scholar, L. J. M. S. B. M. R. B. S. D. G. 2010; PubMed Scopus Google Scholar). data the of GSMs also (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, P. S.A. D. 2009; PubMed Scopus Google Scholar) and a of studies that suggested that GSMs target the J.L. Sagi S.A. Smith T.E. S. Das P. Koo E.H. Golde T.E. J. PubMed Scopus Google Scholar, S. Eriksen J.L. Sagi S.A. Pietrzik C.U. V. Fauq A. Golde T.E. Koo E.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. H. T. T. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. M.S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. S. A. M.P. M. 2004; PubMed Scopus Google Scholar). of APP not to substrate binding of GSMs R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). mutations the GSM binding site in APP not the of GSMs R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). both familial and mutations at the γ-secretase cleavage site domain the GSM responses R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). FAD mutations in PS in response to NSAIDs, lowering of Aβ42 is not effective for the of mutants (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, E. S. C. A. M. Koo E.H. Pietrzik C.U. Baumann K. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. Cottrell B.A. S. T. Ladd T.B. H. S. R. Torpey Pietrzik C.U. Golde T.E. J. Baumann K. Koo E.H. S. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). was for aggressive mutations with disease that a of Aβ42, such as the PS1 L166P which was also to the potent compound GSM-1 (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). These data suggested that in aggressive mutations γ-secretase in a that the to the Aβ42-lowering of GSMs. we report the that Aβ42 can be for many sulindac pathogenic and PS mutations by GSM-1 and other second-generation GSMs. a positive Aβ42-lowering response not depends on the mutation but also on the particular FAD mutations in in particular aggressive are to low potency Aβ42-lowering drugs such as sulindac and others (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, E. S. C. A. M. Koo E.H. Pietrzik C.U. Baumann K. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. Cottrell B.A. S. T. Ladd T.B. H. S. R. Torpey Pietrzik C.U. Golde T.E. J. Baumann K. Koo E.H. S. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). PS1 L166P and PS2 also to be to the more potent second-generation compound GSM-1 (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). data have to the that Aβ42 generation may not be by GSMs for FAD we found that but not all aggressive mutations in PS can be by GSM-1. The mutants identified the PS Although Aβ42 responses to GSM-1 in and on the particular of the of Aβ42 the PS1 L166P and PS2 a few other PS mutations identified to to GSM-1. homologous PS1 and PS2 mutations display differential suggesting that a positive Aβ42 response depends on the particular mutation and its spatial environment in many the Aβ42 response for sulindac and GSM-1 suggesting that modulators also very with respect to drug GSM-1 may have a to the GSM binding site than for the low potency drug sulindac sulfide, thus being more potent than this PS mutations may the binding of a low potency GSM but not of a potency thus affecting the of GSMs on Aβ42 that the PS1 L166P mutation is an as to GSM-1 to other potent GSMs of different structural the PS1 Leu-166 residue to be critical for GSM-1 as a of the mutations at to GSM-1. the a Aβ42 response to in the response of the PS mutants with respect to the to lower Aβ42, sulindac and GSM-1 in all an of with being the more potent the of generation by GSM-1 also than that of sulindac The of is that for a mutation Aβ42 be by a can be (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, E. Cottrell B.A. S. T. Ladd T.B. H. S. R. Torpey Pietrzik C.U. Golde T.E. J. Baumann K. Koo E.H. S. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar), is also not by our can probably be resolved second-generation GSM to binding which may on mechanistic the of such are to GSM binding mutation has been identified that the of GSMs on all Aβ species, which be that a GSM binding site was Although our data thus, also not fully GSMs target the substrate, the and/or both, the differential responses of GSMs to PS mutations may be more with a GSM binding site(s) in γ-secretase, probably the catalytic subunit PS With respect to this we found PS2 attenuated Aβ42 responses to GSM-1 as with all PS2 mutants to GSM-1. These in GSM response the may also be to with an GSM binding Aβ42 responses of PS mutants that positive for GSM-1 also positive for other potent second-generation compounds and (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). the mutants such as PS1 L166P also to the and the compounds. may be as compounds are different GSM-1, that the GSM binding site is and can thus also probably by an GSMs with of GSM-1-responsive mutants was that besides Aβ42, Aβ40 also be in was very for the PS1 for which the species in response to GSM-1, and also for the and compounds The of Aβ40 generation is for GSMs of potent compound classes (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, E. B. M. H. H. K. J. 2010; PubMed Scopus Google of PS mutants for which inhibition of Aβ40 generation was and Aβ40 responses to response to in a our data show that the of many PS mutations to low potency drugs can be overcome by GSMs with such as GSM-1 for a GSMs that may for AD also be to patients FAD by PS mutations a of with respect to the particular mutation by the is that our data the that not all AD are for studies with GSMs and thus have to be that depends both on the particular GSM to be and the particular PS as PS1 L166P and PS2 R. T. S.A. J. D. L. H. S. Haass C. B. C. C. M. EMBO PubMed Scopus Google Scholar, A.M. Ozmen L. B. P. M. H. C. G. H. Jacobsen H. J. 23: PubMed Google Scholar) may not be for GSM in (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), other AD such as the with similarly Aβ M.A. G. H. D. Haass C. M. A. Science. 2008; PubMed Scopus Google Scholar) are to be for the in of GSMs in of PS mutations and Aβ42 responses to GSMs in a IntroductionThe amyloid β-peptide (Aβ) 4The abbreviations used are: Aβamyloid β-peptideADAlzheimer diseaseAPPβ-amyloid precursor proteinFADfamilial Alzheimer diseaseGSMγ-secretase modulatorNSAIDnon-steroidal anti-inflammatory drugPSpresenilinTMDtransmembrane domainTris-BicineTris-N,N-bis(2-hydroxyethyl)glycine. is a 37–43-amino acid secreted peptide and an invariant pathological hallmark of Alzheimer disease (AD). The 42-amino acid variant Aβ42 has been suggested to be causative for the disease by triggering the amyloid cascade, a sequence of pathogenic events that ultimately leads to neurodegeneration and dementia in affected patients (1Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (10796) Google Scholar). The pathogenic peptide is generated by a sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretase (2Haass C. EMBO J. 2004; 23: 483-488Crossref PubMed Scopus (479) Google Scholar). After β-secretase cleavage, γ-secretase cleaves the C-terminal fragment of APP that is left in the membrane by an intramembrane cleavage to release the various Aβ species (3Steiner H. Fluhrer R. Haass C. J. Biol. Chem. 2008; 283: 29627-29631Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 4Tolia A. De Strooper B. Semin. Cell Dev. Biol. 2009; 20: 211-218Crossref PubMed Scopus (75) Google Scholar, 5Wolfe M.S. Semin. Cell Dev. Biol. 2009; 20: 219-224Crossref PubMed Scopus (73) Google Scholar). Although Aβ42 is normally a minor species produced by this cleavage besides the major Aβ40 species, its production is enhanced by familial AD (FAD) mutations in presenilin (PS) 1 and PS2, the catalytic component of γ-secretase (6Steiner H. Curr. Alzheimer Res. 2008; 5: 147-157Crossref PubMed Scopus (34) Google Scholar), as well as by a subset of FAD mutations in APP. Targeting β- and γ-secretase by specific inhibitors is one of the current approaches toward an effective AD treatment (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar). With respect to γ-secretase, however, γ-secretase inhibitors also block the cleavage of Notch1, a major physiological γ-secretase substrate and, thus, the generation of the Notch1 intracellular domain (NICD), which is a crucial signaling molecule controlling cell differentiation (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar). Interfering with the cleavage of this substrate accounts for adverse side effects in animal studies (7Tomita T. Expert Rev. Neurother. 2009; 9: 661-679Crossref PubMed Scopus (119) Google Scholar) and probably in humans as well. γ-Secretase modulators (GSMs) that selectively lower Aβ42, such as a subset of non-steroidal anti-inflammatory drugs (NSAIDs), are considered to be a safer approach than using inhibitors of γ-secretase that target the active site of the protease. These compounds lower Aβ42 generation without affecting Notch1 intracellular domain generation, thus precluding potential Notch-related side effects (8Weggen S. Eriksen J.L. Das P. Sagi S.A. Wang R. Pietrzik C.U. Findlay K.A. Smith T.E. Murphy M.P. Bulter T. Kang D.E. Marquez-Sterling N. Golde T.E. Koo E.H. Nature. 2001; 414: 212-216Crossref PubMed Scopus (1317) Google Scholar). More potent drugs than NSAIDs, such as the NSAID-like GSM-1 and others effective in the nanomolar range, have been recently identified (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. Chem. 2008; 283: 677-683Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar).The precise mechanistic mode(s) of action as well as the binding site(s) of GSMs, being on the substrate, the enzyme, and/or both, has not yet been fully resolved and may also differ for various types of GSMs (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 11Kukar T.L. Ladd T.B. Bann M.A. Fraering P.C. Narlawar R. Maharvi G.M. Healy B. Chapman R. Welzel A.T. Price R.W. Moore B. Rangachari V. Cusack B. Eriksen J. Jansen-West K. Verbeeck C. Yager D. Eckman C. Ye W. Sagi S. Cottrell B.A. Torpey J. Rosenberry T.L. Fauq A. Wolfe M.S. Schmidt B. Walsh D.M. Koo E.H. Golde T.E. Nature. 2008; 453: 925-929Crossref PubMed Scopus (271) Google Scholar). Many GSMs typically shift the cleavage specificity of γ-secretase such that the inhibition of Aβ42 generation is accompanied by an generation of the (8Weggen S. Eriksen J.L. Das P. Sagi S.A. Wang R. Pietrzik C.U. Findlay K.A. Smith T.E. Murphy M.P. Bulter T. Kang D.E. Marquez-Sterling N. Golde T.E. Koo E.H. Nature. 2001; 414: 212-216Crossref PubMed Scopus (1317) Google Scholar). GSMs, such as the NSAID an of and the and species is J.L. Sagi S.A. Smith T.E. S. Das P. Koo E.H. Golde T.E. J. PubMed Scopus Google Scholar). to Aβ42, the by and also the and Aβ40 as well as the species can be by GSMs, suggesting a of GSM action R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). modulators have also been identified that the Aβ42 species lowering the species T. Murphy M.P. Eriksen J.L. Sagi S.A. S. Smith T.E. Ladd T. M.A. R. J. M. S. Das P. Fauq A. Koo E.H. Golde T.E. PubMed Scopus Google Scholar). GSMs to target the substrate by binding to a of the Aβ domain in the of the APP domain T.L. Ladd T.B. Bann M.A. Fraering P.C. Narlawar R. Maharvi G.M. Healy B. Chapman R. Welzel A.T. Price R.W. Moore B. Rangachari V. Cusack B. Eriksen J. Jansen-West K. Verbeeck C. Yager D. Eckman C. Ye W. Sagi S. Cottrell B.A. Torpey J. Rosenberry T.L. Fauq A. Wolfe M.S. Schmidt B. Walsh D.M. Koo E.H. Golde T.E. Nature. 2008; 453: 925-929Crossref PubMed Scopus (271) Google Scholar). More the binding of GSMs to Aβ has been to of the APP lowering Aβ42 generation P. A. D. C. R. M. D. G. EMBO J. PubMed Scopus Google Scholar, L. J. M. S. B. M. R. B. S. D. G. 2010; PubMed Scopus Google Scholar). data the of GSMs also (10Kounnas M.Z. Danks A.M. Cheng S. Tyree C. Ackerman E. Zhang X. Ahn K. Nguyen P. Comer D. Mao L. Yu C. Pleynet D. Digregorio P.J. Velicelebi G. Stauderman K.A. Comer W.T. Mobley W.C. Li Y.M. Sisodia S.S. Tanzi R.E. Wagner S.L. Neuron. 2010; 67: 769-780Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, P. S.A. D. 2009; PubMed Scopus Google Scholar) and a of studies that suggested that GSMs target the J.L. Sagi S.A. Smith T.E. S. Das P. Koo E.H. Golde T.E. J. PubMed Scopus Google Scholar, S. Eriksen J.L. Sagi S.A. Pietrzik C.U. V. Fauq A. Golde T.E. Koo E.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. H. T. T. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. M.S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. S. A. M.P. M. 2004; PubMed Scopus Google Scholar). of APP not to substrate binding of GSMs R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). mutations the GSM binding site in APP not the of GSMs R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). both familial and mutations at the γ-secretase cleavage site domain the GSM responses R.M. A. Fukumori A. E. Haass C. Steiner H. J. Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). FAD mutations in PS in response to NSAIDs, lowering of Aβ42 is not effective for the of mutants (9Page R.M. Baumann K. Tomioka M. Pérez-Revuelta B.I. Fukumori A. Jacobsen H. Flohr A. Luebbers T. Ozmen L. Steiner H. Haass C. J. Biol. 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These data suggested that in aggressive mutations γ-secretase in a that the to the Aβ42-lowering of GSMs. we report the that Aβ42 can be for many sulindac pathogenic and PS mutations by GSM-1 and other second-generation GSMs. a positive Aβ42-lowering response not depends on the mutation but also on the particular
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