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Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia

Title
Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia
Authors
Seo, Jin SooKritskiy, OlegWatson, L. AshleyBarker, Scarlett JDey, DilipRaja, Waseem K.Lin, Yuan-TaKo, TakCho, SukheePenney, JaySilva, M. CatarinaSheridan, StevenLucente, DianeGusella, James F.Dickerson, BradHaggarty, StepheTsai, Li-Huei
DGIST Authors
Seo, Jin Soo
Issue Date
2017-10
Citation
JOURNAL OF NEUROSCIENCE, 37(41), 9917-9924
Type
Article
Article Type
Article
Keywords
Alzheimer&aposs diseasecerebral organoidscyclin-dependent kinase 5iPSCsisogenictauopathy
ISSN
0270-6474
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) withΔp35KI 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. © 2017 the authors.
URI
http://hdl.handle.net/20.500.11750/6169
DOI
10.1523/JNEUROSCI.0621-17.2017
Publisher
SOC NEUROSCIENCE
Related Researcher
Files:
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Collection:
ETC1. Journal Articles


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