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dc.contributor.authorSilva, M. Catarina
dc.contributor.authorSheridan, Steven D.
dc.contributor.authorLucente, Diane
dc.contributor.authorGusella, James F.
dc.contributor.authorDickerson, Bradford C.
dc.contributor.authorHaggarty, Stephen J.
dc.contributor.authorTsai, Li-Huei
dc.contributor.authorSeo, Jinsoo
dc.contributor.authorKritskiy, Oleg
dc.contributor.authorWatson, Lauren Ashley
dc.contributor.authorBarker, Scarlett Jazmine
dc.contributor.authorDey, Dilip Chandra
dc.contributor.authorRaja, Waseem K
dc.contributor.authorLin, Yuan-Ta
dc.contributor.authorKo, Tak
dc.contributor.authorCho, Sukhee
dc.contributor.authorPenney, Jay
dc.date.accessioned2018-04-03T15:05:30Z
dc.date.available2018-04-03T15:05:30Z
dc.date.issued2017-10
dc.date.submitted2017-08
dc.identifier.issn0270-6474
dc.identifier.issn1529-2401
dc.identifier.urihttp://hdl.handle.net/1721.1/114504
dc.description.abstractIncreased 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.en_US
dc.description.sponsorshipNational Institutes of Health (Grant R37NS051874)en_US
dc.description.sponsorshipRobert A. and Renee E. Belfer Family Foundationen_US
dc.description.sponsorshipNeurodegeneration Consortiumen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1523/JNEUROSCI.0621-17.2017en_US
dc.rightsArticle 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.en_US
dc.sourceSociety for Neuroscienceen_US
dc.titleInhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementiaen_US
dc.typeArticleen_US
dc.identifier.citationSeo, 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 Authorsen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentPicower Institute for Learning and Memoryen_US
dc.contributor.mitauthorSeo, Jinsoo
dc.contributor.mitauthorKritskiy, Oleg
dc.contributor.mitauthorWatson, Lauren Ashley
dc.contributor.mitauthorBarker, Scarlett Jazmine
dc.contributor.mitauthorDey, Dilip Chandra
dc.contributor.mitauthorRaja, Waseem K
dc.contributor.mitauthorLin, Yuan-Ta
dc.contributor.mitauthorKo, Tak
dc.contributor.mitauthorCho, Sukhee
dc.contributor.mitauthorPenney, Jay
dc.contributor.mitauthorTsai, Li-Huei
dc.relation.journalThe Journal of Neuroscienceen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2017-12-11T12:52:06Z
dspace.orderedauthorsSeo, Jinsoo; Kritskiy, Oleg; Watson, L. Ashley; Barker, Scarlett J.; Dey, Dilip; Raja, Waseem K.; Lin, Yuan-Ta; Ko, Tak; Cho, Sukhee; Penney, Jay; Silva, M. Catarina; Sheridan, Steven D.; Lucente, Diane; Gusella, James F.; Dickerson, Bradford C.; Haggarty, Stephen J.; Tsai, Li-Hueien_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-2237-1569
dc.identifier.orcidhttps://orcid.org/0000-0002-5452-2352
dc.identifier.orcidhttps://orcid.org/0000-0002-2461-1135
dc.identifier.orcidhttps://orcid.org/0000-0001-5607-113X
dc.identifier.orcidhttps://orcid.org/0000-0003-1262-0592
mit.licensePUBLISHER_POLICYen_US


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