Lack Of Endogenous Tau Rescues Impaired Adult Neurogenesis In The Dentate Gyrus In FTLD-17 Human Mutant Tau Transgenic Mice
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1
Free University of Brussels, Belgium
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2
INSERM U1172 Centre de Recherche Jean Pierre Aubert, France
Impaired adult hippocampal neurogenesis is a feature of several neurodegenerative diseases, including Alzheimer’s disease and tauopathies, and might contribute to defects in learning and memory in these diseases. The relationship between pathological tau proteins, a common key-lesion in these diseases, and reduced adult neurogenesis is still unclear. To assess the interference of pathological tau with this process, we analysed adult neurogenesis in the hippocampal dentate gyrus in wild-type, tauKO, FTLD- 17 mutant tau Tg30 (G272V/P301S) and Tg30/tauKO mice. Using unbiased stereological methods, we observed a significant reduction of the granular cell layer volume and of the granule cells number in the dentate gyrus (DG) of mutant tau Tg30 mice (but not in Tg30/tauKO mice) at 12 months of age. The number of neuronal progenitors expressing the immature markers DCX or 3R-tau (only expressed in WT and Tg30) was reduced in Tg30 but not in Tg30/tauKO mice. The number of cells expressing the proliferation marker Ki-67 in the subgranular zone (SGZ) was also reduced in Tg30, but not in Tg30/tauKO mice. The human mutant tau protein was expressed in mature granule cells from Tg30 and Tg30 /tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors. The density of GFAP positive astrocytes and of CD11b positive microglial cells was similar in mice with those different genotypes. These results show that impairment of adult hippocampal neurogenesis in a FTLD-17 mutant tau mice results from a decrease of proliferation, reducing the pool of neuronal precursors. The absence of mutant tau expression in precursors cells suggests that this alteration is cell non-autonomous, and might be due to modifications of the microenvironment of the neurogenic niche. Interestingly, expression of endogenous wild-type tau is necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis is rescued in Tg30/tauKO mice. This observation suggests that the development of a tau pathology in granule cells of the DG might be responsible for a reduction of adult neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that the reduction of tau expression rescues this impairment.
Résumé en français: Titre: L'absence du tau murin endogène annule l'effet négatif de l'expression du tau humain muté sur la neurogenèse adulte chez la souris transgénique.
Nous avons analysé la neurogenèse adulte au niveau de l’hippocampe, siège de la mémoire, qui est la première impactée lors de la maladie d’Alzheimer. Plusieurs modèles murins dans lesquels la protéine tau murine est soit absente, soit exprimée avec une isoforme tau humaine mutée, ont été étudiés. Les souris exprimant la protéine tau murine et la protéine tau humaine mutée, montrent une diminution de la neurogenèse. Chez les souris n’exprimant que la protéine tau humaine mutée, la neurogenèse n’est pas modifiée. L’absence du tau murin empêcherait l’effet négatif de la protéine tau humaine mutée sur la neurogenèse adulte.
Keywords:
adult neurogenesis,
Alzheimer's disease,
mice models,
Tauopathy,
Hippocampus
Conference:
Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.
Presentation Type:
e-posters
Topic:
NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE
Citation:
Houben
S,
Leroy
K,
Ando
K,
Yilmaz
Z,
Buee
L and
Brion
J
(2019). Lack Of Endogenous Tau Rescues Impaired Adult Neurogenesis In The Dentate Gyrus In FTLD-17 Human Mutant Tau Transgenic Mice.
Front. Neurosci.
Conference Abstract:
Belgian Brain Congress 2018 — Belgian Brain Council.
doi: 10.3389/conf.fnins.2018.95.00001
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Received:
07 Aug 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Miss. Sarah Houben, Free University of Brussels, Brussels, Belgium, Sarah.Houben@ulb.ac.be
Prof. Jean-Pierre Brion, Free University of Brussels, Brussels, Belgium, jpbrion@ulb.ac.be