BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Evidence suggests that β-amyloid (Aβ) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer’s disease (AD). However, the causal link between Aβ and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2007-04-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996106003172 |
| _version_ | 1818724670553194496 |
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| author | Masuo Ohno Sarah L. Cole Marina Yasvoina Jie Zhao Martin Citron Robert Berry John F. Disterhoft Robert Vassar |
| author_facet | Masuo Ohno Sarah L. Cole Marina Yasvoina Jie Zhao Martin Citron Robert Berry John F. Disterhoft Robert Vassar |
| author_sort | Masuo Ohno |
| collection | DOAJ |
| description | Evidence suggests that β-amyloid (Aβ) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer’s disease (AD). However, the causal link between Aβ and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the β-secretase (BACE1) not only abrogates Aβ generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Aβ ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD. |
| first_indexed | 2024-12-17T21:30:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:30:06Z |
| publishDate | 2007-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-4c60bc4225294b41a4c3251f0b9713042022-12-21T21:31:55ZengElsevierNeurobiology of Disease1095-953X2007-04-01261134145BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic miceMasuo Ohno0Sarah L. Cole1Marina Yasvoina2Jie Zhao3Martin Citron4Robert Berry5John F. Disterhoft6Robert Vassar7Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3008, USA; Corresponding authors. M. Ohno is to be contacted at present address, Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Fax: +1 845 398 5422. R. Vassar, fax: +1 312 503 7912.Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USADepartment of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USADepartment of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USADepartment of Neuroscience, Amgen Inc., Thousand Oaks, CA 91320, USADepartment of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USADepartment of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3008, USADepartment of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611-3008, USA; Corresponding authors. M. Ohno is to be contacted at present address, Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Fax: +1 845 398 5422. R. Vassar, fax: +1 312 503 7912.Evidence suggests that β-amyloid (Aβ) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer’s disease (AD). However, the causal link between Aβ and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the β-secretase (BACE1) not only abrogates Aβ generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Aβ ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.http://www.sciencedirect.com/science/article/pii/S0969996106003172Alzheimer’s diseaseβ-Amyloid (Aβ)β-SecretaseBACE1 knockoutTg6799Gliosis |
| spellingShingle | Masuo Ohno Sarah L. Cole Marina Yasvoina Jie Zhao Martin Citron Robert Berry John F. Disterhoft Robert Vassar BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice Neurobiology of Disease Alzheimer’s disease β-Amyloid (Aβ) β-Secretase BACE1 knockout Tg6799 Gliosis |
| title | BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice |
| title_full | BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice |
| title_fullStr | BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice |
| title_full_unstemmed | BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice |
| title_short | BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice |
| title_sort | bace1 gene deletion prevents neuron loss and memory deficits in 5xfad app ps1 transgenic mice |
| topic | Alzheimer’s disease β-Amyloid (Aβ) β-Secretase BACE1 knockout Tg6799 Gliosis |
| url | http://www.sciencedirect.com/science/article/pii/S0969996106003172 |
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