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Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains - PubMed

Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains

Susana Boluda et al. Acta Neuropathol. 2015 Feb.

Abstract

Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer's disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6-9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD.

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Figures

Fig. 1
Fig. 1

Biochemical analysis of the pathological tau protein-enriched extracts obtained from human brains with a neuropathological diagnosis of CBD, AD, DSAD and a non-disease normal control brain used for injection into PS19 Tg mice. SDS gel stained with Coomassie blue (a). Immunoblots stained with 17025 (b) and PHF1 (c)

Fig. 2
Fig. 2

Development of cell type-specific tau inclusions after injection of CBD-Tau- or DSAD-Tau-enriched protein extracts into the brains of PS19 mice. a, c, e AT8-positive oligodendroglial inclusions developed in the fimbria of the hippocampus on the injected side at 1 month after the injection of CBD-Tau. b, d, f AT8-positive inclusions developed in the perikarya of neurons of the hippocampus of DSAD-Tau-injected mice. c A higher magnification of the square boxed area in (a) is shown in (c) demonstrating AT8-positive tau inclusions in many oligodendrocytes of the fimbria (c). The inset in (c) shows a detail of the oligodendrocytes indicated by the black arrows. d A higher magnification of the square boxed area in (b) is shown in (d) demonstrating the absence of tau inclusions in the oligodendrocytes of the fimbria (d) which contrasts with the CBD-Tau-injected mice. e Higher magnification of the rectangular boxed area in (a) demonstrating only rare intraneuronal inclusions in the CA3 region of the hippocampus (e). In f, where a higher magnification of the rectangular boxed area in (b) is depicted, there is abundance of perikaryal AT8 inclusions in CA3 of the hippocampus. Scale bar, upper row 500 μm; middle and bottom rows 50 μm

Fig. 3
Fig. 3

Tau inclusions that developed in PS19 mice injected with CBD-Tau increased in intensity and spread to regions distal from the injection site with increasing post-injection survival times. a Microphotographs of brain sections immunostained with AT8 showing the fimbria, alveus/external capsule and stratum radiatum ipsilateral to the injection site in the PS19 mice at 1, 3, 6 months post-injection. Scale bar, upper row 200 μm; middle and lower rows 100 μm. b Heatmaps of coronal sections showing the CBD-Tau-induced glial tau pathology at the same time points as in (a). Quantification [1 month (n = 6), 3 months (n = 6) and 6 months (n = 6)] was conducted as described in “Materials and methods” to generate these heatmaps. Each heatmap panel represents pathology distribution in one of the three coronal planes (Bregma −1.22, −2.18 and −2.92). Left column shows sagittal view of the selected coronal planes indicated by a red line. Blue stars indicate injection site

Fig. 4
Fig. 4

Neuronal tau inclusions developed in PS19 mice injected with AD-Tau and DSAD-Tau and they increased in abundance, intensity and spread to regions distal from the injected site with increasing post-injection survival times. a Microscopic images of brain sections of DSAD-Tau-injected mice. The images are representative of the dentate gyrus, CA1 and entorhinal cortex of the side ipsilateral to the injection following IHC with AT8 at 1, 3, 6 months post-injection. Scale bars 75 μm. b Heatmaps of coronal sections of tau pathology seen after injection at the same time points as in (a). Semiquantitative analysis of AT8 pathology was performed in AD-Tau- and DSAD-Tau-injected mice and combined in the heatmap here [1 month (n = 8), 3 months (n = 8) and 6 months (n = 8)]. Each panel represents pathology distribution in one of the five coronal planes (Bregma 0.98, −1.22 −2.18, −2.92 and −4.48 mm) at different time points after injection. Left column shows sagittal view of the selected coronal planes that are indicated by a red line. Blue stars indicate injection site

Fig. 5
Fig. 5

There is neuron loss in the CA3 region of PS19 mice injected with AD-Tau and DSAD-Tau at 3 and 6 months post-injection. a The upper row of images show H&E stained low-power microphotographs of the hippocampus contralateral to the AD-Tau injection in PS19 mice at 1, 3, and 6 months post-injection. The microphotographs in the lower row show higher magnification images of the boxed areas in the upper row. Scale bar, upper row 500 μm; lower row 100 μm. b Quantification of the neurons in the CA3 region of PS19 mice injected with non-pathological or control (CTRL-Tau) human brain extract versus enriched CBD-Tau or AD-Tau and DSAD-Tau fractions. Error bars indicate SEM; ***p < 0.001, as determined by one-way ANOVA and Tukey’s multiple-comparison test, with n = 2 in CTRL-Tau at 1 month and 6 months; n = 5 in CBD-Tau at 1 month and 3 months; n = 6 in CBD-Tau at 6 months; and n = 7 in AD/DSAD-Tau at 1, 3 and 6 months

Fig. 6
Fig. 6

Dose-dependent increase in tau pathology in PS19 mice after the injection of human brain derived DSAD-Tau. At 1 month after injection, the burden of tau pathology increases and the distribution of pathology is more extensive throughout brain structures following injections of increasing amounts of injected pathological tau. Heatmaps of coronal sections of tau pathology after injections of serial dilutions of DSAD-Tau into PS19 mice. Each panel represents pathology distribution in one of the five coronal planes (Bregma 0.98, −1.22 −2.18, −2.92 and −4.48 mm) at 1 month post-injection (n = 3 for each dose of DSAD-Tau). Left column shows sagittal view of the selected coronal planes that are indicated by a red line. Blue stars indicate injection site

Fig. 7
Fig. 7

Tau inclusions in PS19 mice after injection of CBD-Tau and DSAD-Tau show properties that recapitulate their human disease counterparts. Microphotographs are of brain sections stained with mAbs AT8, MC1 and TG3 to detect abnormal phosphorylation (AT8) and conformational (MC1, TG3) changes in pathological tau and ThS histochemistry to demonstrate the amyloid properties of the inclusions. Shown here are the fimbria of Tg mice injected with CBD-Tau at 1 month, 3 and 6 months post-injection (upper three rows) and CA3 of Tg mice injected with DSAD-Tau extracts at 1 month after injection (lower row). Scale bars 50 μm

Fig. 8
Fig. 8

Accumulation of tau pathology in oligodendrocytes and astrocytes in PS19 mice injected with CBD-Tau parallels pathology of sporadic CBD in humans. a Brain sections stained with mAb AT8 in the far left column, while the 3 columns to the right show double immunofluorescence with Olig2 (green in nucleus), AT8 (red in cytoplasm and neurites) and merged images in the fimbria of a PS19 mouse 6 months after injection (upper row) and subcortical white matter of the cingulate gyrus in a sporadic CBD case (lower row). b Brain sections stained with mAb AT8 and double immunofluorescence with GFAP (green), AT8 (red) and merged images in the stratum radiatum of the hippocampus of a PS19 mouse 6 months after injection (upper row) and gray matter of the parietal cortex of a sporadic CBD case (lower row). Scale bar 50 μm

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