Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1)
Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been im...
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2012
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| Online Access: | http://hdl.handle.net/1721.1/71221 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1826191494472531968 |
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| author | Giusti-Rodriguez, Paola Gao, Jun Graff, Johannes Rei, Damien Soda, Takahiro Tsai, Li-Huei |
| author2 | Whitaker College of Health Sciences and Technology |
| author_facet | Whitaker College of Health Sciences and Technology Giusti-Rodriguez, Paola Gao, Jun Graff, Johannes Rei, Damien Soda, Takahiro Tsai, Li-Huei |
| author_sort | Giusti-Rodriguez, Paola |
| collection | MIT |
| description | Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD. |
| first_indexed | 2024-09-23T08:56:45Z |
| format | Article |
| id | mit-1721.1/71221 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:56:45Z |
| publishDate | 2012 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/712212024-03-21T20:13:37Z Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of β-Secretase (BACE1) Giusti-Rodriguez, Paola Gao, Jun Graff, Johannes Rei, Damien Soda, Takahiro Tsai, Li-Huei Whitaker College of Health Sciences and Technology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Tsai, Li-Huei Giusti-Rodriguez, Paola Gao, Jun Graff, Johannes Rei, Damien Soda, Takahiro Tsai, Li-Huei Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD. National Institutes of Health (U.S.) (Grant NIH R01NS051874) Ruth L. Kirschstein National Research Service Award (Predoctoral Fellowship F31GM80055-03) 2012-06-27T17:50:26Z 2012-06-27T17:50:26Z 2011-11 2011-09 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/71221 Giusti-Rodriguez, P. et al. “Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1).” Journal of Neuroscience 31.44 (2011): 15751–15756. Web. 27 June 2012. https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1523/jneurosci.3588-11.2011 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience SFN |
| spellingShingle | Giusti-Rodriguez, Paola Gao, Jun Graff, Johannes Rei, Damien Soda, Takahiro Tsai, Li-Huei Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title | Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title_full | Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title_fullStr | Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title_full_unstemmed | Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title_short | Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1) |
| title_sort | synaptic deficits are rescued in the p25 cdk5 model of neurodegeneration by the reduction of beta secretase bace1 |
| url | http://hdl.handle.net/1721.1/71221 https://orcid.org/0000-0003-1262-0592 |
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