Alzheimer's disease and other tauopathies have been linked to impaired adult hippocampal neurogenesis, which may be a factor in these diseases' learning and memory deficits. We examined adult neurogenesis in the hippocampal dentate gyrus of wild-type mice, Tg30 mice expressing an FTDP-17 mutant tau, and the same Tg30 mice deficient for mouse tau (Tg30/tauKO) in order to determine the impact of tau pathology, a frequent key-lesion in these diseases, on adult hippocampal neurogenesis. Unbiased stereological techniques were used to measure the density of the granular layer, the number of granule cells, and the number of neuronal precursors expressing the immature markers DCX or 3R-tau in the dentate gyrus (DG). It was also examined how neurogenic markers co-localized with human mutant tau.
The volume of the granular layer and the number of granule cells were significantly reduced in mutant tau Tg30 mice, but not in Tg30/tauKO animals. The number of cells expressing the proliferation marker Ki-67 and the number of neuronal precursors displaying the immaturity markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) in the neurogenic sub granular zone of the DG were decreased in Tg30 but not in Tg30/tauKOmice.
In comparison to Tg30 mice, Tg30/tauKO mice had reduced levels of soluble human phosphate and phosphate-positive cell density in the DG. In Tg30 and Tg30/tauKO mice, the human mutant tau was expressed in adult granule cells but not in Sox2 positive neural stem cells, DCX positive neuronal progenitors, or immature newborn neurons. These findings show that adult hippocampus neurogenesis is impaired in tau FTDP-17 mutant mice due to a reduction in proliferation that affects the pool of neural progenitors.
These mutant tau animals did not express mutant tau in precursor cells, indicating that this neurogenic defect is not cell-autonomous. As this decreased adult neurogenesis was restored by reducing tau expression in Tg30/tauKO mice, it is interesting to note that expression of endogenous wild-type tau in mature granule cells was required to see this harmful effect of human mutant tau. These findings imply that human tauopathies also reduce adult hippocampal neurogenesis through the development of tau pathology in dentate gyrus granule cells by inhibiting proliferation of neural progenitors, and that reducing tau expression may be a way to reverse this impairment.
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