Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia
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Author(s)
Silva, M. Catarina
Sheridan, Steven D.
Lucente, Diane
Gusella, James F.
Dickerson, Bradford C.
Haggarty, Stephen J.
Tsai, Li-Huei
Seo, Jinsoo
Kritskiy, Oleg
Watson, Lauren Ashley
Date Issued
October 2017
Journal
The Journal of Neuroscience
Publisher
Society for Neuroscience
Citation
Seo, Jinsoo, et al. “Inhibition of P25/Cdk5 Attenuates Tauopathy in Mouse and IPSC Models of Frontotemporal Dementia.” The Journal of Neuroscience, vol. 37, no. 41, Oct. 2017, pp. 9917–24. © 2017 the Authors
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Final published version
Abstract
Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer’s disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer’s disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L: Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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DOI of Published Version
https://doi.org/10.1523/JNEUROSCI.0621-17.2017
