Human tau expression reduces adult neurogenesis in a mouse model of tauopathy

Abstract

Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the present study, we used the genomic-based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of the disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in 2 different brain regions by as early as 2 months of age, before the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not because of enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared with non-transgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies.

Keywords: Adult neurogenesis; MAPT; Mouse; Tau; Tauopathy; hTau.

Figure 1. Neurogenesis is decreased in the hTau mouse

(A, C) Staining was examined in the subgranular (A) and subventricular (C) zones in 2 month old, 6 month old, and 12 month old mice. Green in the subgranular zone (A) is Dcx and in the subventricular zone (C) is Ki67. Red is NeuN in both. (B, D) Staining was quantified at each time point in the subgranular (B) and subventricular (D) zones. N=6 animals. Scale bar indicates 100 μm. * refers to p<0.05, ** refers to p<0.01, and *** refers to p<0.001

Figure 1. Neurogenesis is decreased in the hTau mouse

(A, C) Staining was examined in the subgranular (A) and subventricular (C) zones in 2 month old, 6 month old, and 12 month old mice. Green in the subgranular zone (A) is Dcx and in the subventricular zone (C) is Ki67. Red is NeuN in both. (B, D) Staining was quantified at each time point in the subgranular (B) and subventricular (D) zones. N=6 animals. Scale bar indicates 100 μm. * refers to p<0.05, ** refers to p<0.01, and *** refers to p<0.001

Figure 1. Neurogenesis is decreased in the hTau mouse

(A, C) Staining was examined in the subgranular (A) and subventricular (C) zones in 2 month old, 6 month old, and 12 month old mice. Green in the subgranular zone (A) is Dcx and in the subventricular zone (C) is Ki67. Red is NeuN in both. (B, D) Staining was quantified at each time point in the subgranular (B) and subventricular (D) zones. N=6 animals. Scale bar indicates 100 μm. * refers to p<0.05, ** refers to p<0.01, and *** refers to p<0.001

Figure 1. Neurogenesis is decreased in the hTau mouse

(A, C) Staining was examined in the subgranular (A) and subventricular (C) zones in 2 month old, 6 month old, and 12 month old mice. Green in the subgranular zone (A) is Dcx and in the subventricular zone (C) is Ki67. Red is NeuN in both. (B, D) Staining was quantified at each time point in the subgranular (B) and subventricular (D) zones. N=6 animals. Scale bar indicates 100 μm. * refers to p<0.05, ** refers to p<0.01, and *** refers to p<0.001

Figure 2. Proliferation in the dentate gyrus region is reduced in the hTau animal

BrdU incorporation was examined in 2 month old mice (A). Dcx is in green, and BrdU is in red. Quantification of staining at 2 months (B). N=6 animals. Scale bar indicates 100 μm. * refers to p<0.05

Figure 3. Tau expressed in the neurogenic niche is abnormally phosphorylated in the hTau mouse

Tau phosphorylation was examined using AT8 in 2 month old mice in the subgranular (A) and subventricular (B) zones. Dcx is in green, and AT8 is in red. Note differences in scale bar. Tau phosphorylation in 2 month old mice was also examined through Western blotting using AT8 and GAPDH (C).

Figure 4. In vitro culture of neurospheres show a proliferative defect in hTau mice

Neurospheres were cultured from WT and hTau mice at embryonic and adult ages. Images of embryonic neurospheres (A) were taken at 5 days and 12 days in culture. Note differences in scale bar. Quantification of neurosphere size from embryonic culture (B) and adult culture (C). N=6 animals. *** refers to p<0.001