Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo
Nicastrin is an integral member of PS-complexes that perform γ-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing γ-secretase activity by reducing levels of functional PS-complexes is suggested as a p...
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| Format: | Article |
| Language: | English |
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Elsevier
2007-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996106002403 |
| _version_ | 1819119509365063680 |
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| author | Sonya Brijbassi Zareen Amtul Susan Newbigging David Westaway Peter St George-Hyslop Richard F. Rozmahel |
| author_facet | Sonya Brijbassi Zareen Amtul Susan Newbigging David Westaway Peter St George-Hyslop Richard F. Rozmahel |
| author_sort | Sonya Brijbassi |
| collection | DOAJ |
| description | Nicastrin is an integral member of PS-complexes that perform γ-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing γ-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on γ-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in γ-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP γ-secretase cleavage, APP C-terminal fragments or β-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and γ-secretase activity as a therapeutic strategy for Alzheimer's disease. |
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| format | Article |
| id | doaj.art-7127bc756ab64a9c800bfd0f78622a7f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:05:54Z |
| publishDate | 2007-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-7127bc756ab64a9c800bfd0f78622a7f2022-12-21T18:36:25ZengElsevierNeurobiology of Disease1095-953X2007-02-01252291296Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivoSonya Brijbassi0Zareen Amtul1Susan Newbigging2David Westaway3Peter St George-Hyslop4Richard F. Rozmahel5Department of Biochemistry, University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, CanadaDepartment of Biochemistry, University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaCentre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, CanadaCentre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, CanadaDepartment of Biochemistry, University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Corresponding author. Lawson Health Research Institute, LRCP Room A4-837, 790 Commissioner's Rd E., London, ON, Canada N6A4L6. Fax: +1 519 685 8641.Nicastrin is an integral member of PS-complexes that perform γ-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing γ-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on γ-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in γ-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP γ-secretase cleavage, APP C-terminal fragments or β-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and γ-secretase activity as a therapeutic strategy for Alzheimer's disease.http://www.sciencedirect.com/science/article/pii/S0969996106002403Alzheimer's diseaseNicastrin presenilinγ-secretaseAmyloid precursor protein |
| spellingShingle | Sonya Brijbassi Zareen Amtul Susan Newbigging David Westaway Peter St George-Hyslop Richard F. Rozmahel Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo Neurobiology of Disease Alzheimer's disease Nicastrin presenilin γ-secretase Amyloid precursor protein |
| title | Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo |
| title_full | Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo |
| title_fullStr | Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo |
| title_full_unstemmed | Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo |
| title_short | Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo |
| title_sort | excess of nicastrin in brain results in heterozygosity having no effect on endogenous app processing and amyloid peptide levels in vivo |
| topic | Alzheimer's disease Nicastrin presenilin γ-secretase Amyloid precursor protein |
| url | http://www.sciencedirect.com/science/article/pii/S0969996106002403 |
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