Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum
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 a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/2/718 |
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| author | Pol Andrés-Benito Margarita Carmona Mónica Jordán Joaquín Fernández-Irigoyen Enrique Santamaría José Antoni del Rio Isidro Ferrer |
| author_facet | Pol Andrés-Benito Margarita Carmona Mónica Jordán Joaquín Fernández-Irigoyen Enrique Santamaría José Antoni del Rio Isidro Ferrer |
| author_sort | Pol Andrés-Benito |
| collection | DOAJ |
| description | 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 <i>mapt</i> or <i>MAPT</i> 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. |
| first_indexed | 2024-03-10T01:19:00Z |
| format | Article |
| id | doaj.art-6e92fc175d6d46aaa27344f89b51cda2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:19:00Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6e92fc175d6d46aaa27344f89b51cda22023-11-23T14:03:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123271810.3390/ijms23020718Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD InoculumPol Andrés-Benito0Margarita Carmona1Mónica Jordán2Joaquín Fernández-Irigoyen3Enrique Santamaría4José Antoni del Rio5Isidro Ferrer6Neuropathology Group, Institute of Biomedical Research, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, SpainNeuropathology Group, Institute of Biomedical Research, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, SpainCIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, L’Hospitalet de Llobregat, 08907 Barcelona, SpainClinical Neuroproteomics Unit, Proteomics Platform, Proteored-ISCIII, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), diSNA, 31008 Pamplona, SpainClinical Neuroproteomics Unit, Proteomics Platform, Proteored-ISCIII, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), diSNA, 31008 Pamplona, SpainCIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, L’Hospitalet de Llobregat, 08907 Barcelona, SpainNeuropathology Group, Institute of Biomedical Research, IDIBELL, L’Hospitalet de Llobregat, 08907 Barcelona, SpainSeveral 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 <i>mapt</i> or <i>MAPT</i> 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.https://www.mdpi.com/1422-0067/23/2/718host tauseeding and spreading3Rtau and 4RtauhTauAlzheimer’s diseasetauopathies |
| spellingShingle | Pol Andrés-Benito Margarita Carmona Mónica Jordán Joaquín Fernández-Irigoyen Enrique Santamaría José Antoni del Rio Isidro Ferrer Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum International Journal of Molecular Sciences host tau seeding and spreading 3Rtau and 4Rtau hTau Alzheimer’s disease tauopathies |
| title | Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum |
| title_full | Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum |
| title_fullStr | Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum |
| title_full_unstemmed | Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum |
| title_short | Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum |
| title_sort | host tau genotype specifically designs and regulates tau seeding and spreading and host tau transformation following intrahippocampal injection of identical tau ad inoculum |
| topic | host tau seeding and spreading 3Rtau and 4Rtau hTau Alzheimer’s disease tauopathies |
| url | https://www.mdpi.com/1422-0067/23/2/718 |
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