Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model
The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway...
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2023-03-01
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| author | Lea Langer Horvat Ena Španić Popovački Mirjana Babić Leko Klara Zubčić Luka Horvat Maja Mustapić Patrick R. Hof Goran Šimić |
| author_facet | Lea Langer Horvat Ena Španić Popovački Mirjana Babić Leko Klara Zubčić Luka Horvat Maja Mustapić Patrick R. Hof Goran Šimić |
| author_sort | Lea Langer Horvat |
| collection | DOAJ |
| description | The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human <i>MAPT</i> (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD. |
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| spelling | doaj.art-ae5386b7891540c59cddaabf9ba0eb682023-11-17T18:25:11ZengMDPI AGBiomedicines2227-90592023-03-01114100410.3390/biomedicines11041004Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy ModelLea Langer Horvat0Ena Španić Popovački1Mirjana Babić Leko2Klara Zubčić3Luka Horvat4Maja Mustapić5Patrick R. Hof6Goran Šimić7Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Molecular Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, CroatiaLaboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USANash Family Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaThe tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human <i>MAPT</i> (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD.https://www.mdpi.com/2227-9059/11/4/1004Alzheimer’s diseasecognitionneurofibrillary degenerationspatial working memorytau fibrilstau oligomers |
| spellingShingle | Lea Langer Horvat Ena Španić Popovački Mirjana Babić Leko Klara Zubčić Luka Horvat Maja Mustapić Patrick R. Hof Goran Šimić Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model Biomedicines Alzheimer’s disease cognition neurofibrillary degeneration spatial working memory tau fibrils tau oligomers |
| title | Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model |
| title_full | Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model |
| title_fullStr | Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model |
| title_full_unstemmed | Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model |
| title_short | Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model |
| title_sort | anterograde and retrograde propagation of inoculated human tau fibrils and tau oligomers in a non transgenic rat tauopathy model |
| topic | Alzheimer’s disease cognition neurofibrillary degeneration spatial working memory tau fibrils tau oligomers |
| url | https://www.mdpi.com/2227-9059/11/4/1004 |
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