Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17
Background: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in...
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MDPI AG
2023-10-01
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| author | Debby Van Dam Femke Valkenburg Kristof Van Kolen Isabel Pintelon Jean-Pierre Timmermans Peter Paul De Deyn |
| author_facet | Debby Van Dam Femke Valkenburg Kristof Van Kolen Isabel Pintelon Jean-Pierre Timmermans Peter Paul De Deyn |
| author_sort | Debby Van Dam |
| collection | DOAJ |
| description | Background: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models. Methods: We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms. The spatiotemporal development of tau pathology was investigated immunohistochemically. Levels of sarkosyl-insoluble paired helical filaments were determined via a MesoScale Discovery biomarker assay. Results: Neuromotor impairments developed from age 3 months in both models. On electron microscopy, spinal cord neurofibrillary pathology was visible in mice aged 3 months; however, AT8 immunoreactivity was not yet observed in Tau58/4 mice. Behavioral abnormalities and memory deficits occurred at a later stage (>9 months) when tau pathology was fully disseminated throughout the brain. Spatiotemporally, tau pathology spread from the spinal cord via the midbrain to the frontal cortex, while the hippocampus was relatively spared, thus explaining the late onset of cognitive deficits. Conclusions: Our findings indicate the face and construct validity of both Tau58 models, which may provide new, valuable insights into the pathologic effects of tau species in vivo and may consequently facilitate the development of new therapeutic targets to delay or halt neurodegenerative processes occurring in tauopathies. |
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| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-10T21:06:54Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-6c1945a425ec48379ee799912401d6bb2023-11-19T17:07:14ZengMDPI AGLife2075-17292023-10-011310208810.3390/life13102088Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17Debby Van Dam0Femke Valkenburg1Kristof Van Kolen2Isabel Pintelon3Jean-Pierre Timmermans4Peter Paul De Deyn5Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk, 2610 Antwerp, BelgiumLaboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk, 2610 Antwerp, BelgiumNeuroscience Department, Janssen Research and Development, 2340 Beerse, BelgiumLaboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, 2610 Antwerp, BelgiumLaboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, 2610 Antwerp, BelgiumLaboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk, 2610 Antwerp, BelgiumBackground: The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models. Methods: We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms. The spatiotemporal development of tau pathology was investigated immunohistochemically. Levels of sarkosyl-insoluble paired helical filaments were determined via a MesoScale Discovery biomarker assay. Results: Neuromotor impairments developed from age 3 months in both models. On electron microscopy, spinal cord neurofibrillary pathology was visible in mice aged 3 months; however, AT8 immunoreactivity was not yet observed in Tau58/4 mice. Behavioral abnormalities and memory deficits occurred at a later stage (>9 months) when tau pathology was fully disseminated throughout the brain. Spatiotemporally, tau pathology spread from the spinal cord via the midbrain to the frontal cortex, while the hippocampus was relatively spared, thus explaining the late onset of cognitive deficits. Conclusions: Our findings indicate the face and construct validity of both Tau58 models, which may provide new, valuable insights into the pathologic effects of tau species in vivo and may consequently facilitate the development of new therapeutic targets to delay or halt neurodegenerative processes occurring in tauopathies.https://www.mdpi.com/2075-1729/13/10/2088tauopathyfrontotemporal dementiaAlzheimer’s diseasemotor dysfunctioncognitive deficitsbehavioral disinhibition |
| spellingShingle | Debby Van Dam Femke Valkenburg Kristof Van Kolen Isabel Pintelon Jean-Pierre Timmermans Peter Paul De Deyn Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 Life tauopathy frontotemporal dementia Alzheimer’s disease motor dysfunction cognitive deficits behavioral disinhibition |
| title | Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 |
| title_full | Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 |
| title_fullStr | Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 |
| title_full_unstemmed | Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 |
| title_short | Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17 |
| title_sort | behavioral and neuropathological phenotyping of the tau58 2 and tau58 4 transgenic mouse models for ftdp 17 |
| topic | tauopathy frontotemporal dementia Alzheimer’s disease motor dysfunction cognitive deficits behavioral disinhibition |
| url | https://www.mdpi.com/2075-1729/13/10/2088 |
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