Host tau genotype specifically designs and regulates tau seeding and spreading and host tau transformation following intrahippocampal injection of identical tau AD inoculum
| dc.contributor.author | Andrés Benito, Pol | |
| dc.contributor.author | Carmona, Margarita | |
| dc.contributor.author | Jordán, Mónica | |
| dc.contributor.author | Fernández Irigoyen, Joaquín | |
| dc.contributor.author | Santamaría Martínez, Enrique | |
| dc.contributor.author | Río, José Antonio del | |
| dc.contributor.author | Ferrer, Isidro | |
| dc.contributor.department | Ciencias de la Salud | es_ES |
| dc.contributor.department | Osasun Zientziak | eu |
| dc.date.accessioned | 2022-04-07T12:10:20Z | |
| dc.date.available | 2022-04-07T12:10:20Z | |
| dc.date.issued | 2022 | |
| dc.description.abstract | Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula. | en |
| dc.description.sponsorship | The project leading to these results received funding from the La Caixa Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 to IF; it was also supported by the Ministry of Economy and Competitiveness, Institute of Health Carlos III (ISCIII) (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FISPI17/000809 to IF; and the IntraCIBERNED 2019 collaborative project to IF and JADR. This work was also co-financed by ERDF under the program Interreg Poctefa: RedPrion 148/16; ERDF [148/16]. | en |
| dc.format.extent | 22 p. | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.doi | 10.3390/ijms23020718 | |
| dc.identifier.issn | 1661-6596 | |
| dc.identifier.uri | https://academica-e.unavarra.es/handle/2454/42668 | |
| dc.language.iso | eng | en |
| dc.publisher | MDPI | |
| dc.relation.ispartof | International Journal of Molecular Sciences, 23 (2), 2022 | en |
| dc.relation.publisherversion | https://doi.org/10.3390/ijms23020718 | |
| dc.rights | © 2022 by the authors. Creative Commons Attribution 4.0 International | en |
| dc.rights.accessRights | info:eu-repo/semantics/openAccess | |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
| dc.subject | 3Rtau and 4Rtau | en |
| dc.subject | Alzheimer’s disease | en |
| dc.subject | Host tau | en |
| dc.subject | HTau | en |
| dc.subject | Seeding and spreading | en |
| dc.subject | Tauopathies | en |
| dc.title | Host tau genotype specifically designs and regulates tau seeding and spreading and host tau transformation following intrahippocampal injection of identical tau AD inoculum | en |
| dc.type | info:eu-repo/semantics/article | |
| dc.type.version | info:eu-repo/semantics/publishedVersion | |
| dspace.entity.type | Publication | |
| relation.isAuthorOfPublication | 86d1b76e-4790-40b1-a3ec-72331c5c6199 | |
| relation.isAuthorOfPublication | abacfd17-2b93-4d99-bae2-52053d57401e | |
| relation.isAuthorOfPublication.latestForDiscovery | 86d1b76e-4790-40b1-a3ec-72331c5c6199 |