Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice
<p>Abstract</p> <p>Background</p> <p>The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a r...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2012-01-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://www.molecularneurodegeneration.com/content/7/1/1 |
| _version_ | 1819043062764011520 |
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| author | Chu Jin Giannopoulos Phillip F Ceballos-Diaz Carolina Golde Todd E Pratico Domenico |
| author_facet | Chu Jin Giannopoulos Phillip F Ceballos-Diaz Carolina Golde Todd E Pratico Domenico |
| author_sort | Chu Jin |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice.</p> <p>Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology.</p> <p>Results</p> <p>Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2.</p> <p>Conclusions</p> <p>These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.</p> |
| first_indexed | 2024-12-21T09:50:49Z |
| format | Article |
| id | doaj.art-94c7078db55d4472a7c103f2d766416e |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T09:50:49Z |
| publishDate | 2012-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-94c7078db55d4472a7c103f2d766416e2022-12-21T19:08:11ZengBMCMolecular Neurodegeneration1750-13262012-01-0171110.1186/1750-1326-7-1Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP miceChu JinGiannopoulos Phillip FCeballos-Diaz CarolinaGolde Todd EPratico Domenico<p>Abstract</p> <p>Background</p> <p>The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice.</p> <p>Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology.</p> <p>Results</p> <p>Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2.</p> <p>Conclusions</p> <p>These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.</p>http://www.molecularneurodegeneration.com/content/7/1/1Alzheimer's diseaseanimal modelamyloid beta5-Lipoxygenase |
| spellingShingle | Chu Jin Giannopoulos Phillip F Ceballos-Diaz Carolina Golde Todd E Pratico Domenico Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice Molecular Neurodegeneration Alzheimer's disease animal model amyloid beta 5-Lipoxygenase |
| title | Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice |
| title_full | Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice |
| title_fullStr | Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice |
| title_full_unstemmed | Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice |
| title_short | Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice |
| title_sort | adeno associated virus mediated brain delivery of 5 lipoxygenase modulates the ad like phenotype of app mice |
| topic | Alzheimer's disease animal model amyloid beta 5-Lipoxygenase |
| url | http://www.molecularneurodegeneration.com/content/7/1/1 |
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