Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation

Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited Aβ production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4-CD8-CD44+CD25+ precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing. Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-secretase inhibitor LY-411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited Aβ production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4-CD8-CD44+CD25+ precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411,575, which is a very weak γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing. Alzheimer disease (AD) 1The abbreviations used are: AD, Alzheimer disease; APP, amyloid precursor protein; NICD, Notch intracellular domain; DN, double negative; Aβ, β-amyloid peptide; LY-D, inactive diastereoisomer of LY-411,575. is the third most common cause of death and the leading cause of dementia in the United States (1Ewbank D.C. Am. J. Public Health. 1999; 89: 90-92Crossref PubMed Scopus (66) Google Scholar). Although the exact cause of AD is still unknown, the etiology of the disease is almost certainly linked to several neuropathological hallmarks observed in the brains of AD victims, particularly extracellular neuritic amyloid plaques and intracellular neurofibrillary tangles (2Arnold S.E. Hyman B.T. Flory J. Damasio A.R. Van Hoesen G.W. Cereb. Cortex. 1991; 1: 103-116Crossref PubMed Scopus (1138) Google Scholar, 3Games D. Adams D. Alessandrini R. Barbour R. Berthelette P. Blackwell C. Carr T. Clemens J. Donaldson T. Gillespie F. Nature. 1995; 373: 523-527Crossref PubMed Scopus (2246) Google Scholar, 4Dickson D.W. Crystal H.A. Bevona C. Honer W. Vincent I. Davies P. Neurobiol. Aging. 1995; 16: 285-298Crossref PubMed Scopus (364) Google Scholar). Although both of these neuropathological lesions probably contribute to progressive neuronal cell death in AD, the proximal lesion appears to be the amyloid plaques and their principal component, the Aβ peptides. A large body of evidence strongly suggests that overproduction, aggregation, and/or plaque deposition of the Aβ peptides, particularly Aβ42, are central to the pathogenesis of AD (reviewed in Ref. 5Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (11018) Google Scholar). In fact, two recent studies of patients immunized against the Aβ42 peptide have provided the first preliminary clinical evidence that Aβ does indeed contribute to the cognitive decline in AD patients (6Nicoll J.A. Wilkinson D. Holmes C. Steart P. Markham H. Weller R.O. Nat. Med. 2003; 9: 448-452Crossref PubMed Scopus (1294) Google Scholar, 7Hock C. Konietzko U. Streffer J.R. Tracy J. Signorell A. Muller-Tillmanns B. Lemke U. Henke K. Moritz E. Garcia E. Wollmer M.A. Umbricht D. de Quervain D.J. Hofmann M. Maddalena A. Papassotiropoulos A. Nitsch R.M. Neuron. 2003; 38: 547-554Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar). The Aβ peptides are produced by the sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretase. γ-Secretase is a complex composed of at least four proteins, namely presenilins (presenilin 1 or -2), nicastrin, PEN-2, and APH-1 (8De Strooper B. Neuron. 2003; 38: 9-12Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar). Presenilin 1 and -2 have been proposed to be the novel aspartyl proteases responsible for the catalytic activity of γ-secretase (9Wolfe M.S. Xia W. Ostaszewski B.L. Diehl T.S. Kimberly W.T. Selkoe D.J. Nature. 1999; 398: 513-517Crossref PubMed Scopus (1692) Google Scholar, 10Zhang Z. Nadeau P. Song W. Donoviel D. Yuan M. Bernstein A. Yankner B.A. Nat. Cell Biol. 2000; 2: 463-465Crossref PubMed Scopus (359) Google Scholar). Because of the essential role of γ-secretase in the generation of Aβ peptides, γ-secretase inhibitors may be useful in the treatment of AD. To date, several γ-secretase inhibitors have been identified that lower Aβ production in intact cells and cell-free systems (reviewed in Ref. 11Josien H. Curr. Opin. Drug Discovery Dev. 2002; 5: 513-525PubMed Google Scholar). In addition, two potent γ-secretase inhibitors, N-N-(3,5-difluorophenacetyl-l-alanyl)-S-phenylglycine tert-butyl ester (DAPT) and LY-411,575, have also been shown to decrease Aβ production after administration to transgenic mice overexpressing human APP (12Dovey H.F. John V. Anderson J.P. Chen L.Z. de Saint Andrieu P. Fang L.Y. Freedman S.B. Folmer B. Goldbach E. Holsztynska E.J. Hu K.L. Johnson-Wood K.L. Kennedy S.L. Kholodenko D. Knops J.E. Latimer L.H. Lee M. Liao Z. Lieberburg I.M. Motter R.N. Mutter L.C. Nietz J. Quinn K.P. Sacchi K.L. Seubert P.A. Shopp G.M. Thorsett E.D. Tung J.S. Wu J. Yang S. Yin C.T. Schenk D.B. May P.C. Altstiel L.D. Bender M.H. Boggs L.N. Britton T.C. Clemens J.C. Czilli D.L. Dieckman-McGinty D.K. Droste J.J. Fuson K.S. Gitter B.D. Hyslop P.A. Johnstone E.M. Li W.-Y. Little S.P. Mabry T.E. Miller F.D. Ni B. Nissen J.S. Porter W.J. Potts B.D. Reel J.K. Stephenson D. Su Y. Shipley L.A. Whitesitt C.A. Yin T. Audia J.E. J. Neurochem. 2001; 76: 173-181Crossref PubMed Scopus (797) Google Scholar, 13May P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google Scholar, 14Lanz T.A. Himes C.S. Pallante G. Adams L. Yamazaki S. Amore B. Merchant K.M. J. Pharmacol. Exp. Ther. 2003; 305: 864-871Crossref PubMed Scopus (144) Google Scholar). It is appreciated now that APP is not the only substrate for γ-secretase. Other proteins that have been shown to be substrates for γ-secretase cleavage include Notch (16De Strooper B. Annaert W. Cupers P. Saftig P. Craessaerts K. J.S. V. M.S. W.J. A. R. Nature. 1999; 398: PubMed Scopus Google and the Notch and T. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google T.E. G. Science. 2001; PubMed Scopus Google S. M. M. C. A. D. J. H. C. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google and P. J. G. A. S. V. L. P. S. Z. T. J. 2002; PubMed Scopus Google Scholar). The cleavage of Notch by γ-secretase has been most Notch an role in cell and particularly development I. Dev. PubMed Scopus Google Scholar, S. R.J. Science. 1999; PubMed Scopus Google Scholar, J. 1995; PubMed Google Scholar). Notch is by several and and is by a of and γ-Secretase the cleavage which a as the Notch intracellular The to the as a J.A. R. Nature. PubMed Scopus Google Scholar, G. A. Full Text Full Text PDF PubMed Scopus Google Scholar). expected role in Notch γ-secretase inhibitors have been shown to production in A. T. M.S. 2003; PubMed Scopus Google Scholar). In Notch appears to be for the differentiation of T and B (reviewed in Ref. D. J.A. D.J. J.C. 2002; Full Text Full Text PDF PubMed Scopus Google and γ-secretase inhibitors the number and differentiation at an in thymic Su D. M.S. R. U. S. A. 2001; PubMed Scopus Google Scholar, P. M.S. R.M. U. S. A. 2001; PubMed Scopus Google Scholar). These that in addition to their benefit in AD, γ-secretase inhibitors may have because of inhibition of the proteolytic processing of Notch other that are for a of both the and the of γ-secretase inhibition, are the in vivo biological consequences of γ-secretase inhibitors the inhibition of APP processing and Aβ are to the and of γ-secretase inhibition as an approach to the treatment of AD. In treatment of mice the potent γ-secretase inhibitor LY-411,575 P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google was used to the effects of γ-secretase inhibition on Aβ production and to consequences of γ-secretase A that is a weak γ-secretase inhibitor was used to effects of LY-411,575 that are to γ-secretase inhibition the effects of the and and a diastereoisomer to as were to Wu J. Tung J.S. Thorsett E.D. M.A. Nissen J.S. J. Latimer L.H. John V. Freedman S. Google Scholar). was and the two were by diastereoisomer was and the to the expected The of LY-411,575 and were by and were as in and in for TgCRND8 mice human APP both the and AD the of the M.A. Yang C. P. J. R. J. J. S. G. M. S. C. J. F. C. D. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). TgCRND8 mice on a C57BL/6 were and by the of TgCRND8 or C57BL/6 mice were for or 15 LY-411,575, or the of the mice were by was the in and was were 1 was in and M. K. T. K. M. F. T. S. Y. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). was by the in vivo studies were by the and of the Cell cells human APP both the and have been L. Song L. G. Y. B. E. 2001; PubMed Scopus Google Scholar). was human and a the extracellular was to as J.A. R. Nature. PubMed Scopus Google Scholar). was also in for Aβ and for γ-secretase activity in cells APP have been L. Song L. G. Y. B. E. 2001; PubMed Scopus Google Scholar). cells APP or were of LY-411,575 or for at In the of cells cells were the cell were on a and the was a cleavage The inhibition of production was by In the of cells APP, the was at for to cell and at to the of Aβ and produced in and as as and TgCRND8 were an L. Song L. G. Y. B. E. 2001; PubMed Scopus Google Scholar). Aβ42 was by as L. Song L. E. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). A was used to Aβ42 to the cell the and were tissues in by a cell was as and were the or were by and for at in the and in to to the following were and the was for at in the and were used to To were were on a and The number of cells of was by the of cells in the by the number of or as the of the the intestine, large intestine, and were in in and and for In addition, and large were to goblet were also LY-411,575 a γ-Secretase in and in P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google LY-411,575 is a very potent γ-secretase inhibitor in as by inhibition of Aβ production and in and γ-secretase LY-411,575 is also a potent inhibitor of Notch cleavage A diastereoisomer of LY-411,575, LY-D, was also on the is potent LY-411,575 as an inhibitor of γ-secretase In vivo studies that both 1 and doses of LY-411,575 decreased and and administered to TgCRND8 mice In the administration of the diastereoisomer to TgCRND8 mice had on Aβ in the or The in vivo of LY-411,575 and are not because of because the two after administration not These in and in vivo that LY-411,575 and are to the effects of γ-secretase inhibition the effects that are not to γ-secretase The of the effects of LY-411,575 on and is shown in A of LY-411,575 decreased the observed by 1 after administration The of Aβ was still after the administration of LY-411,575 but to by after administration LY-411,575 also decreased Aβ the was the to the was and the of the was that seen for of Aβ These that of LY-411,575 is to inhibition of γ-secretase. in of γ-Secretase and and were administered to TgCRND8 mice for or 15 days. 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These are γ-Secretase Inhibition treatment of TgCRND8 mice LY-411,575 a marked of the of the A was and was the in the cell number by LY-411,575 In had on A or the number of of intrathymic populations that the number and of by was altered by treatment LY-411,575 but not by treatment the overall decrease in number the number of double double and cells also decreased in a the of and cells the of double cells decreased of LY-411,575 treatment on intrathymic LY-411,575 and and or were administered to TgCRND8 mice for 15 and populations were by as the number of cells in the the number of cells in of the four populations by and The the double on a the of in of the four populations by and The the double on a of on intrathymic The shown are the S.E. and were by as A of the cell that LY-411,575 administration increased the of the and a decrease in the of and a at a very of intrathymic T cell these effects were not observed in in were observed treatment that processing of γ-secretase substrate was by LY-411,575 The of or of was in the inhibition of in the or number of cells were A in the of thymic B cells was observed in not not The of LY-411,575 treatment on peripheral was also In to the in the LY-411,575 treatment altered T cell populations in the peripheral or not LY-411,575 administration cause a in the and number of B cells and a in the and number of B cells in the These that LY-411,575 treatment in a of B cell in the number of B cells were observed in the as No on populations in the or were noted not γ-Secretase Inhibition Cell and in the of TgCRND8 mice LY-411,575 produced in the LY-411,575 a in the number of goblet cells the and large and an increased of the and In one that was in a LY-411,575 treatment also of cells in the the of cell and of In treatment of TgCRND8 mice 1 LY-411,575 or of had on the and recent (12Dovey H.F. John V. Anderson J.P. Chen L.Z. de Saint Andrieu P. Fang L.Y. Freedman S.B. Folmer B. Goldbach E. Holsztynska E.J. Hu K.L. Johnson-Wood K.L. Kennedy S.L. Kholodenko D. Knops J.E. Latimer L.H. Lee M. Liao Z. Lieberburg I.M. Motter R.N. Mutter L.C. Nietz J. Quinn K.P. Sacchi K.L. Seubert P.A. Shopp G.M. Thorsett E.D. Tung J.S. Wu J. Yang S. Yin C.T. Schenk D.B. May P.C. Altstiel L.D. Bender M.H. Boggs L.N. Britton T.C. Clemens J.C. Czilli D.L. Dieckman-McGinty D.K. Droste J.J. Fuson K.S. Gitter B.D. Hyslop P.A. Johnstone E.M. Li W.-Y. Little S.P. Mabry T.E. Miller F.D. Ni B. Nissen J.S. Porter W.J. Potts B.D. Reel J.K. Stephenson D. Su Y. Shipley L.A. Whitesitt C.A. Yin T. Audia J.E. J. Neurochem. 2001; 76: 173-181Crossref PubMed Scopus (797) Google Scholar, 13May P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google Scholar, 14Lanz T.A. Himes C.S. Pallante G. Adams L. Yamazaki S. Amore B. Merchant K.M. J. Pharmacol. Exp. Ther. 2003; 305: 864-871Crossref PubMed Scopus (144) Google have potent γ-secretase inhibitors that are in of Aβ These studies that γ-secretase inhibitors be to the amyloid of AD in and may have clinical in the treatment of the disease. It is now that in addition to APP, γ-secretase several other most Notch Z. Nadeau P. Song W. Donoviel D. Yuan M. Bernstein A. Yankner B.A. Nat. Cell Biol. 2000; 2: 463-465Crossref PubMed Scopus (359) Google Scholar). is the biological consequences of the processing of the γ-secretase substrates in particularly in To the biological effects of the potent γ-secretase inhibitor LY-411,575 P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google were the biological effects of LY-D, a and diastereoisomer of LY-411,575 that is potent as a γ-secretase inhibitor. a the biological effects of γ-secretase inhibition and the biological effects of LY-411,575 that are to γ-secretase In LY-411,575 inhibited Aβ and production It is to that LY-411,575 APP and Notch processing in the potent inhibition of Aβ production in treatment of TgCRND8 mice LY-411,575 decreased and and The of LY-411,575 on Aβ was and the of the on may the that Aβ, particularly Aβ42, in an or and is Aβ, which is likely to be In the of Aβ42, may also the that Aβ42 in TgCRND8 mice are the of these of M.A. Yang C. P. J. R. J. J. S. G. M. S. C. J. F. C. D. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of inhibition of and and by administration of LY-411,575 was the of inhibition seen in studies and not that of γ-secretase activity the of these by and treatment of TgCRND8 mice LY-411,575 or had on a number of tissues the and suggests that the of APP and γ-secretase in tissues (e.g. and may be In effects of treatment of mice LY-411,575 were observed in the and intestine. LY-411,575 treatment a of the of the a of the a decrease in overall thymic and an overall in of the intrathymic populations by and These effects of LY-411,575 are to γ-secretase inhibition, because were not seen following treatment the diastereoisomer of the in a in the of cells in the and and a in the of cells in the and These strongly that LY-411,575 treatment in a of intrathymic differentiation at the at which cells to These are the in effects of γ-secretase inhibitors on maturation observed in thymic Su D. M.S. R. U. S. A. 2001; PubMed Scopus Google Scholar, P. M.S. R.M. U. S. A. 2001; PubMed Scopus Google Scholar, M. de V. 2003; PubMed Scopus Google and the in vivo effects seen after of the F. A. G. M. J. M. 1999; Full Text Full Text PDF PubMed Scopus Google these the at the differentiation and in the and of the γ-secretase inhibitor or in vivo administration and in treatment of thymic γ-secretase inhibitors may for these that altered Notch activity is responsible for the effects of LY-411,575 on the is not to which γ-secretase in Notch and/or M. T.A. D. A. L. U. A. I. 1999; PubMed Scopus Google Scholar). A of altered K.M. Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. I. C.A. G. J. Cell 2002; PubMed Scopus Google or R. I. K. J. 2002; PubMed Scopus Google processing to altered intrathymic differentiation is as well, of LY-411,575 on in the was observed. LY-411,575 treatment also effects on B cell LY-411,575 a in the of B cells in the by of was was not that in vivo γ-secretase inhibition may B T cell the lymphocyte cell populations in the as P. M.S. R.M. U. S. A. 2001; PubMed Scopus Google Scholar, F. A. G. M. J. M. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J.C. 2003; Full Text Full Text PDF Scopus Google Scholar). LY-411,575 inhibited B cell maturation and increased the number of B cells in the overall on cellularity or on other cell treatment not cause these These an role for γ-secretase in B cell development in the recent K. H. K. M. K. A. T. T. Nat. 2002; PubMed Scopus Google Scholar, K. H. S. K. T. T. Y. H. Y. S. T. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, T. S. M. A. T. K. T. G. S. K. E. Y. S. H. 2003; Full Text Full Text PDF PubMed Scopus Google that Notch a role in B cell development in the on the peripheral B cell was in mice F. A. G. M. J. M. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the in B cells in tissues following treatment LY-411,575 may also be because of inhibition of Notch or Notch processing γ-secretase. treatment of TgCRND8 mice LY-411,575 also in the LY-411,575 a of goblet a in in the of the intestine, in one and of the of in the These effects of LY-411,575 are because of inhibition of γ-secretase because were not observed in It was Jordan W.H. Calligaro D.O. E.J. H. M.A. May P.C. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google that a γ-secretase inhibitor effects in intestine. The effects of LY-411,575 on the are probably also because of the inhibition of Notch processing by γ-secretase. in of which is a protein that is in Notch have a very in the J. P. J. M. R. F. P. Nat. 2000; PubMed Scopus Google Scholar). It is likely that the decrease in body and in in TgCRND8 mice LY-411,575 are because of the effects of the on the intestine. It also however, that in the a role in these The study the of γ-secretase inhibitors to Aβ treatment LY-411,575 P.C. Altstiel L. Bender M.H. Boggs L.N. Calligaro D.O. Fuson K.S. Gitter B.D. Hyslop P.A. Jordan W.H. Li W.Y. Mabry T.E. Mark R.J. Ni B. Nissen J.S. Porter W.J. Sorgen S.G. Su Y. Audia J.E. Dovey H.F. Games D. John V. Freedman S.B. Guido T. Johnson-Wood K.L. Khan K. Latimer L.H. Lieberburg I.M. Seubert P.A. Soriano F. Thorsett E.D. Schenk D.B. Abstracts of the Society for Neuroscience 31st Annual Meeting, San Diego, CA, November 10-15, 2001. 2001; : 681Google and several of of mice and that of Aβ production also of amyloid plaques and of cognitive (6Nicoll J.A. Wilkinson D. Holmes C. Steart P. Markham H. Weller R.O. Nat. Med. 2003; 9: 448-452Crossref PubMed Scopus (1294) Google Scholar, 7Hock C. Konietzko U. Streffer J.R. Tracy J. Signorell A. Muller-Tillmanns B. Lemke U. Henke K. Moritz E. Garcia E. Wollmer M.A. Umbricht D. de Quervain D.J. Hofmann M. Maddalena A. Papassotiropoulos A. Nitsch R.M. Neuron. 2003; 38: 547-554Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar). these that γ-secretase inhibitors for the treatment of AD. the study also that γ-secretase inhibitors have several that may of these may be the of LY-411,575 on intrathymic T cell development may not be a in the because the by S.P. J.S. J. Miller Med. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of these be be to T and B cell after γ-secretase inhibitor treatment to the of γ-secretase inhibition on the of the In these studies in the of γ-secretase inhibitors in and effects that be in clinical