Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model
Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampa...
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Elsevier
2019-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119300518 |
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| author | Sarah Houben Karelle Leroy Kunie Ando Zehra Yilmaz Cyprien Widomski Luc Buée Jean-Pierre Brion |
| author_facet | Sarah Houben Karelle Leroy Kunie Ando Zehra Yilmaz Cyprien Widomski Luc Buée Jean-Pierre Brion |
| author_sort | Sarah Houben |
| collection | DOAJ |
| description | Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment. |
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| id | doaj.art-ae2d3ec459a04dc88fe9430d374c9171 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
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| last_indexed | 2024-12-13T14:52:55Z |
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| spelling | doaj.art-ae2d3ec459a04dc88fe9430d374c91712022-12-21T23:41:18ZengElsevierNeurobiology of Disease1095-953X2019-07-01127131141Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy modelSarah Houben0Karelle Leroy1Kunie Ando2Zehra Yilmaz3Cyprien Widomski4Luc Buée5Jean-Pierre Brion6Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, BelgiumLaboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, BelgiumLaboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, BelgiumLaboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, BelgiumLaboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, BelgiumINSERM, U1172. Université de Lille, Lille, FranceLaboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik (Bldg G), B-1070 Brussels, Belgium; Corresponding author at: Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment.http://www.sciencedirect.com/science/article/pii/S0969996119300518Tau proteinsTauopathyAlzheimerNeurogenesisDentate gyrusTau lowering |
| spellingShingle | Sarah Houben Karelle Leroy Kunie Ando Zehra Yilmaz Cyprien Widomski Luc Buée Jean-Pierre Brion Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model Neurobiology of Disease Tau proteins Tauopathy Alzheimer Neurogenesis Dentate gyrus Tau lowering |
| title | Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| title_full | Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| title_fullStr | Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| title_full_unstemmed | Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| title_short | Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| title_sort | genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model |
| topic | Tau proteins Tauopathy Alzheimer Neurogenesis Dentate gyrus Tau lowering |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119300518 |
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