Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of beta-Secretase (BACE1)
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Tsai-Synaptic Deficits Are Rescued.pdf
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Author(s)
Giusti-Rodriguez, Paola
Gao, Jun
Graff, Johannes
Rei, Damien
Soda, Takahiro
Tsai, Li-Huei
Alternative Title
Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of β-Secretase (BACE1)
Date Issued
November 2011
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
Whitaker College of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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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.
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DOI of Published Version
https://doi.org/10.1523/jneurosci.3588-11.2011
