Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia
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 noncleavabl...
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Society for Neuroscience
2018
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| Online Access: | http://hdl.handle.net/1721.1/114504 https://orcid.org/0000-0003-2237-1569 https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0001-5607-113X https://orcid.org/0000-0003-1262-0592 |
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| author | 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 Barker, Scarlett Jazmine Dey, Dilip Chandra Raja, Waseem K Lin, Yuan-Ta Ko, Tak Cho, Sukhee Penney, Jay |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences 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 Barker, Scarlett Jazmine Dey, Dilip Chandra Raja, Waseem K Lin, Yuan-Ta Ko, Tak Cho, Sukhee Penney, Jay |
| author_sort | Silva, M. Catarina |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:15:54Z |
| format | Article |
| id | mit-1721.1/114504 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:15:54Z |
| publishDate | 2018 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/1145042022-09-30T20:00:46Z Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia 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 Barker, Scarlett Jazmine Dey, Dilip Chandra Raja, Waseem K Lin, Yuan-Ta Ko, Tak Cho, Sukhee Penney, Jay Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Seo, Jinsoo Kritskiy, Oleg Watson, Lauren Ashley Barker, Scarlett Jazmine Dey, Dilip Chandra Raja, Waseem K Lin, Yuan-Ta Ko, Tak Cho, Sukhee Penney, Jay Tsai, Li-Huei 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. National Institutes of Health (Grant R37NS051874) Robert A. and Renee E. Belfer Family Foundation Neurodegeneration Consortium 2018-04-03T15:05:30Z 2018-04-03T15:05:30Z 2017-10 2017-08 2017-12-11T12:52:06Z Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/114504 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 https://orcid.org/0000-0003-2237-1569 https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0001-5607-113X https://orcid.org/0000-0003-1262-0592 http://dx.doi.org/10.1523/JNEUROSCI.0621-17.2017 The 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 Society for Neuroscience |
| spellingShingle | 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 Barker, Scarlett Jazmine Dey, Dilip Chandra Raja, Waseem K Lin, Yuan-Ta Ko, Tak Cho, Sukhee Penney, Jay 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 |
| title_full | Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia |
| title_fullStr | Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia |
| title_full_unstemmed | Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia |
| title_short | Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia |
| title_sort | inhibition of p25 cdk5 attenuates tauopathy in mouse and ipsc models of frontotemporal dementia |
| url | http://hdl.handle.net/1721.1/114504 https://orcid.org/0000-0003-2237-1569 https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0001-5607-113X https://orcid.org/0000-0003-1262-0592 |
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