Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain
Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ productio...
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Oxford, UK: Blackwell Science Ltd ; 2001 |
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Online-Ressource |
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2009 ; Blackwell Publishing Journal Backfiles 1879-2005 |
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In: Journal of neurochemistry - Oxford : Wiley-Blackwell, 1956, 76(2001), 1, Seite 0 |
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volume:76 ; year:2001 ; number:1 ; pages:0 |
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| DOI / URN: |
10.1046/j.1471-4159.2001.00012.x |
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NLEJ243146353 |
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| 520 | |a Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. | ||
| 533 | |d 2009 |f Blackwell Publishing Journal Backfiles 1879-2005 |7 |2009|||||||||| | ||
| 650 | 4 | |a amyloid β-peptide | |
| 700 | 1 | |a Dovey, H. F. |4 oth | |
| 700 | 1 | |a John, V. |4 oth | |
| 700 | 1 | |a Anderson, J. P. |4 oth | |
| 700 | 1 | |a Chen, L. Z. |4 oth | |
| 700 | 1 | |a De Saint Andrieu, P. |4 oth | |
| 700 | 1 | |a Fang, L. Y. |4 oth | |
| 700 | 1 | |a Freedman, S. B. |4 oth | |
| 700 | 1 | |a Folmer, B. |4 oth | |
| 700 | 1 | |a Goldbach, E. |4 oth | |
| 700 | 1 | |a Holsztynska, E. J. |4 oth | |
| 700 | 1 | |a Hu, K. L. |4 oth | |
| 700 | 1 | |a Johnson-Wood, K. L. |4 oth | |
| 700 | 1 | |a Kennedy, S. L. |4 oth | |
| 700 | 1 | |a Kholodenko, D. |4 oth | |
| 700 | 1 | |a Knops, J. E. |4 oth | |
| 700 | 1 | |a Latimer, L. H. |4 oth | |
| 700 | 1 | |a Lee, M. |4 oth | |
| 700 | 1 | |a Liao, Z. |4 oth | |
| 700 | 1 | |a Lieberburg, I. M. |4 oth | |
| 700 | 1 | |a Motter, R. N. |4 oth | |
| 700 | 1 | |a Mutter, L. C. |4 oth | |
| 700 | 1 | |a Nietz, J. |4 oth | |
| 700 | 1 | |a Quinn, K. P. |4 oth | |
| 700 | 1 | |a Sacchi, K. L. |4 oth | |
| 700 | 1 | |a Seubert, P. A. |4 oth | |
| 700 | 1 | |a Shopp, G. M. |4 oth | |
| 700 | 1 | |a Thorsett, E. D. |4 oth | |
| 700 | 1 | |a Tung, J. S. |4 oth | |
| 700 | 1 | |a Wu, J. |4 oth | |
| 700 | 1 | |a Yang, S. |4 oth | |
| 700 | 1 | |a Yin, C. T. |4 oth | |
| 700 | 1 | |a Schenk, D. B. |4 oth | |
| 700 | 1 | |a May, P. C. |4 oth | |
| 700 | 1 | |a Altstiel, L. D. |4 oth | |
| 700 | 1 | |a Bender, M. H. |4 oth | |
| 700 | 1 | |a Boggs, L. N. |4 oth | |
| 700 | 1 | |a Britton, T. C. |4 oth | |
| 700 | 1 | |a Clemens, J. C. |4 oth | |
| 700 | 1 | |a Czilli, D. L. |4 oth | |
| 700 | 1 | |a Dieckman-McGinty, D. K. |4 oth | |
| 700 | 1 | |a Droste, J. J. |4 oth | |
| 700 | 1 | |a Fuson, K. S. |4 oth | |
| 700 | 1 | |a Gitter, B. D. |4 oth | |
| 700 | 1 | |a Hyslop, P. A. |4 oth | |
| 700 | 1 | |a Johnstone, E. M. |4 oth | |
| 700 | 1 | |a Li, W-Y. |4 oth | |
| 700 | 1 | |a Little, S. P. |4 oth | |
| 700 | 1 | |a Mabry, T. E. |4 oth | |
| 700 | 1 | |a Miller, F. D. |4 oth | |
| 700 | 1 | |a Ni, B. |4 oth | |
| 700 | 1 | |a Nissen, J. S. |4 oth | |
| 700 | 1 | |a Porter, W. J. |4 oth | |
| 700 | 1 | |a Potts, B. D. |4 oth | |
| 700 | 1 | |a Reel, J. K. |4 oth | |
| 700 | 1 | |a Stephenson, D. |4 oth | |
| 700 | 1 | |a Su, Y. |4 oth | |
| 700 | 1 | |a Shipley, L. A. |4 oth | |
| 700 | 1 | |a Whitesitt, C. A. |4 oth | |
| 700 | 1 | |a Yin, T. |4 oth | |
| 700 | 1 | |a Audia, J. E. |4 oth | |
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10.1046/j.1471-4159.2001.00012.x doi (DE-627)NLEJ243146353 DE-627 ger DE-627 rakwb Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain Oxford, UK Blackwell Science Ltd 2001 Online-Ressource nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. 2009 Blackwell Publishing Journal Backfiles 1879-2005 |2009|||||||||| amyloid β-peptide Dovey, H. F. oth John, V. oth Anderson, J. P. oth Chen, L. Z. oth De Saint Andrieu, P. oth Fang, L. Y. oth Freedman, S. B. oth Folmer, B. oth Goldbach, E. oth Holsztynska, E. J. oth Hu, K. L. oth Johnson-Wood, K. L. oth Kennedy, S. L. oth Kholodenko, D. oth Knops, J. E. oth Latimer, L. H. oth Lee, M. oth Liao, Z. oth Lieberburg, I. M. oth Motter, R. N. oth Mutter, L. C. oth Nietz, J. oth Quinn, K. P. oth Sacchi, K. L. oth Seubert, P. A. oth Shopp, G. M. oth Thorsett, E. D. oth Tung, J. S. oth Wu, J. oth Yang, S. oth Yin, C. T. oth Schenk, D. B. oth May, P. C. oth Altstiel, L. D. oth Bender, M. H. oth Boggs, L. N. oth Britton, T. C. oth Clemens, J. C. oth Czilli, D. L. oth Dieckman-McGinty, D. K. oth Droste, J. J. oth Fuson, K. S. oth Gitter, B. D. oth Hyslop, P. A. oth Johnstone, E. M. oth Li, W-Y. oth Little, S. P. oth Mabry, T. E. oth Miller, F. D. oth Ni, B. oth Nissen, J. S. oth Porter, W. J. oth Potts, B. D. oth Reel, J. K. oth Stephenson, D. oth Su, Y. oth Shipley, L. A. oth Whitesitt, C. A. oth Yin, T. oth Audia, J. E. oth In Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 76(2001), 1, Seite 0 Online-Ressource (DE-627)NLEJ243927584 (DE-600)2020528-4 1471-4159 nnns volume:76 year:2001 number:1 pages:0 http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x text/html Verlag Deutschlandweit zugänglich Volltext GBV_USEFLAG_U ZDB-1-DJB GBV_NL_ARTICLE AR 76 2001 1 0 |
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10.1046/j.1471-4159.2001.00012.x doi (DE-627)NLEJ243146353 DE-627 ger DE-627 rakwb Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain Oxford, UK Blackwell Science Ltd 2001 Online-Ressource nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. 2009 Blackwell Publishing Journal Backfiles 1879-2005 |2009|||||||||| amyloid β-peptide Dovey, H. F. oth John, V. oth Anderson, J. P. oth Chen, L. Z. oth De Saint Andrieu, P. oth Fang, L. Y. oth Freedman, S. B. oth Folmer, B. oth Goldbach, E. oth Holsztynska, E. J. oth Hu, K. L. oth Johnson-Wood, K. L. oth Kennedy, S. L. oth Kholodenko, D. oth Knops, J. E. oth Latimer, L. H. oth Lee, M. oth Liao, Z. oth Lieberburg, I. M. oth Motter, R. N. oth Mutter, L. C. oth Nietz, J. oth Quinn, K. P. oth Sacchi, K. L. oth Seubert, P. A. oth Shopp, G. M. oth Thorsett, E. D. oth Tung, J. S. oth Wu, J. oth Yang, S. oth Yin, C. T. oth Schenk, D. B. oth May, P. C. oth Altstiel, L. D. oth Bender, M. H. oth Boggs, L. N. oth Britton, T. C. oth Clemens, J. C. oth Czilli, D. L. oth Dieckman-McGinty, D. K. oth Droste, J. J. oth Fuson, K. S. oth Gitter, B. D. oth Hyslop, P. A. oth Johnstone, E. M. oth Li, W-Y. oth Little, S. P. oth Mabry, T. E. oth Miller, F. D. oth Ni, B. oth Nissen, J. S. oth Porter, W. J. oth Potts, B. D. oth Reel, J. K. oth Stephenson, D. oth Su, Y. oth Shipley, L. A. oth Whitesitt, C. A. oth Yin, T. oth Audia, J. E. oth In Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 76(2001), 1, Seite 0 Online-Ressource (DE-627)NLEJ243927584 (DE-600)2020528-4 1471-4159 nnns volume:76 year:2001 number:1 pages:0 http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x text/html Verlag Deutschlandweit zugänglich Volltext GBV_USEFLAG_U ZDB-1-DJB GBV_NL_ARTICLE AR 76 2001 1 0 |
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10.1046/j.1471-4159.2001.00012.x doi (DE-627)NLEJ243146353 DE-627 ger DE-627 rakwb Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain Oxford, UK Blackwell Science Ltd 2001 Online-Ressource nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. 2009 Blackwell Publishing Journal Backfiles 1879-2005 |2009|||||||||| amyloid β-peptide Dovey, H. F. oth John, V. oth Anderson, J. P. oth Chen, L. Z. oth De Saint Andrieu, P. oth Fang, L. Y. oth Freedman, S. B. oth Folmer, B. oth Goldbach, E. oth Holsztynska, E. J. oth Hu, K. L. oth Johnson-Wood, K. L. oth Kennedy, S. L. oth Kholodenko, D. oth Knops, J. E. oth Latimer, L. H. oth Lee, M. oth Liao, Z. oth Lieberburg, I. M. oth Motter, R. N. oth Mutter, L. C. oth Nietz, J. oth Quinn, K. P. oth Sacchi, K. L. oth Seubert, P. A. oth Shopp, G. M. oth Thorsett, E. D. oth Tung, J. S. oth Wu, J. oth Yang, S. oth Yin, C. T. oth Schenk, D. B. oth May, P. C. oth Altstiel, L. D. oth Bender, M. H. oth Boggs, L. N. oth Britton, T. C. oth Clemens, J. C. oth Czilli, D. L. oth Dieckman-McGinty, D. K. oth Droste, J. J. oth Fuson, K. S. oth Gitter, B. D. oth Hyslop, P. A. oth Johnstone, E. M. oth Li, W-Y. oth Little, S. P. oth Mabry, T. E. oth Miller, F. D. oth Ni, B. oth Nissen, J. S. oth Porter, W. J. oth Potts, B. D. oth Reel, J. K. oth Stephenson, D. oth Su, Y. oth Shipley, L. A. oth Whitesitt, C. A. oth Yin, T. oth Audia, J. E. oth In Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 76(2001), 1, Seite 0 Online-Ressource (DE-627)NLEJ243927584 (DE-600)2020528-4 1471-4159 nnns volume:76 year:2001 number:1 pages:0 http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x text/html Verlag Deutschlandweit zugänglich Volltext GBV_USEFLAG_U ZDB-1-DJB GBV_NL_ARTICLE AR 76 2001 1 0 |
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10.1046/j.1471-4159.2001.00012.x doi (DE-627)NLEJ243146353 DE-627 ger DE-627 rakwb Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain Oxford, UK Blackwell Science Ltd 2001 Online-Ressource nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. 2009 Blackwell Publishing Journal Backfiles 1879-2005 |2009|||||||||| amyloid β-peptide Dovey, H. F. oth John, V. oth Anderson, J. P. oth Chen, L. Z. oth De Saint Andrieu, P. oth Fang, L. Y. oth Freedman, S. B. oth Folmer, B. oth Goldbach, E. oth Holsztynska, E. J. oth Hu, K. L. oth Johnson-Wood, K. L. oth Kennedy, S. L. oth Kholodenko, D. oth Knops, J. E. oth Latimer, L. H. oth Lee, M. oth Liao, Z. oth Lieberburg, I. M. oth Motter, R. N. oth Mutter, L. C. oth Nietz, J. oth Quinn, K. P. oth Sacchi, K. L. oth Seubert, P. A. oth Shopp, G. M. oth Thorsett, E. D. oth Tung, J. S. oth Wu, J. oth Yang, S. oth Yin, C. T. oth Schenk, D. B. oth May, P. C. oth Altstiel, L. D. oth Bender, M. H. oth Boggs, L. N. oth Britton, T. C. oth Clemens, J. C. oth Czilli, D. L. oth Dieckman-McGinty, D. K. oth Droste, J. J. oth Fuson, K. S. oth Gitter, B. D. oth Hyslop, P. A. oth Johnstone, E. M. oth Li, W-Y. oth Little, S. P. oth Mabry, T. E. oth Miller, F. D. oth Ni, B. oth Nissen, J. S. oth Porter, W. J. oth Potts, B. D. oth Reel, J. K. oth Stephenson, D. oth Su, Y. oth Shipley, L. A. oth Whitesitt, C. A. oth Yin, T. oth Audia, J. E. oth In Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 76(2001), 1, Seite 0 Online-Ressource (DE-627)NLEJ243927584 (DE-600)2020528-4 1471-4159 nnns volume:76 year:2001 number:1 pages:0 http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x text/html Verlag Deutschlandweit zugänglich Volltext GBV_USEFLAG_U ZDB-1-DJB GBV_NL_ARTICLE AR 76 2001 1 0 |
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10.1046/j.1471-4159.2001.00012.x doi (DE-627)NLEJ243146353 DE-627 ger DE-627 rakwb Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain Oxford, UK Blackwell Science Ltd 2001 Online-Ressource nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. 2009 Blackwell Publishing Journal Backfiles 1879-2005 |2009|||||||||| amyloid β-peptide Dovey, H. F. oth John, V. oth Anderson, J. P. oth Chen, L. Z. oth De Saint Andrieu, P. oth Fang, L. Y. oth Freedman, S. B. oth Folmer, B. oth Goldbach, E. oth Holsztynska, E. J. oth Hu, K. L. oth Johnson-Wood, K. L. oth Kennedy, S. L. oth Kholodenko, D. oth Knops, J. E. oth Latimer, L. H. oth Lee, M. oth Liao, Z. oth Lieberburg, I. M. oth Motter, R. N. oth Mutter, L. C. oth Nietz, J. oth Quinn, K. P. oth Sacchi, K. L. oth Seubert, P. A. oth Shopp, G. M. oth Thorsett, E. D. oth Tung, J. S. oth Wu, J. oth Yang, S. oth Yin, C. T. oth Schenk, D. B. oth May, P. C. oth Altstiel, L. D. oth Bender, M. H. oth Boggs, L. N. oth Britton, T. C. oth Clemens, J. C. oth Czilli, D. L. oth Dieckman-McGinty, D. K. oth Droste, J. J. oth Fuson, K. S. oth Gitter, B. D. oth Hyslop, P. A. oth Johnstone, E. M. oth Li, W-Y. oth Little, S. P. oth Mabry, T. E. oth Miller, F. D. oth Ni, B. oth Nissen, J. S. oth Porter, W. J. oth Potts, B. D. oth Reel, J. K. oth Stephenson, D. oth Su, Y. oth Shipley, L. A. oth Whitesitt, C. A. oth Yin, T. oth Audia, J. E. oth In Journal of neurochemistry Oxford : Wiley-Blackwell, 1956 76(2001), 1, Seite 0 Online-Ressource (DE-627)NLEJ243927584 (DE-600)2020528-4 1471-4159 nnns volume:76 year:2001 number:1 pages:0 http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x text/html Verlag Deutschlandweit zugänglich Volltext GBV_USEFLAG_U ZDB-1-DJB GBV_NL_ARTICLE AR 76 2001 1 0 |
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functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain |
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Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain |
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Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. |
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Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. |
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Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. Development of such novel functional γ-secretase inhibitors will enable a clinical examination of the Aβ hypothesis that Aβ peptide drives the neuropathology observed in Alzheimer's disease. |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">NLEJ243146353</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230506090201.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">120427s2001 xx |||||o 00| ||und c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1046/j.1471-4159.2001.00012.x</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)NLEJ243146353</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="a">Oxford, UK</subfield><subfield code="b">Blackwell Science Ltd</subfield><subfield code="c">2001</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">z</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zu</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Converging lines of evidence implicate the beta-amyloid peptide (Aβ) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Aβ production by functionally inhibiting γ-secretase, the activity responsible for the carboxy-terminal cleavage required for Aβ production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Aβ production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APPV717F reduces brain levels of Aβ in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain Aβin vivo. 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