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Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model.

Cook C, Kang SS, Carlomagno Y, Lin WL, Yue M, Kurti A, Shinohara M, Jansen-West K, Perkerson E, Castanedes-Casey M, Rousseau L, Phillips V, Bu G, Dickson DW, Petrucelli L, Fryer JD - Hum. Mol. Genet. (2015)

Bottom Line: However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95.Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments.Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.

No MeSH data available.


Related in: MedlinePlus

Widespread expression of human tau in AAV1-TauP301L model of tauopathy. Human tau-specific antibody (E1) reveals high level of expression throughout the brain and hippocampus in AAV1-TauP301L-injected (b and e) and rTg4510 mice (c and f), whereas AAV1-GFP-injected mice are negative (a and d). AAV1-TauP301L is also highly expressed throughout the hippocampal network (g–l), as well as other regions of the brain (s–x). The pattern of human tau expression in the hippocampal network (m–r) and other regions of the brain (y-dd) is shown in comparison with rTg4510 model. Scale bar in a–c equals 2 mm; scale bar in d–f equals 200 µm; scale bar in g–dd equals 100 µm.
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DDV336F1: Widespread expression of human tau in AAV1-TauP301L model of tauopathy. Human tau-specific antibody (E1) reveals high level of expression throughout the brain and hippocampus in AAV1-TauP301L-injected (b and e) and rTg4510 mice (c and f), whereas AAV1-GFP-injected mice are negative (a and d). AAV1-TauP301L is also highly expressed throughout the hippocampal network (g–l), as well as other regions of the brain (s–x). The pattern of human tau expression in the hippocampal network (m–r) and other regions of the brain (y-dd) is shown in comparison with rTg4510 model. Scale bar in a–c equals 2 mm; scale bar in d–f equals 200 µm; scale bar in g–dd equals 100 µm.

Mentions: To assess the ability to model tauopathy with somatic brain transgenesis with AAV1-TauP301L on postnatal day 0, mice were harvested at 6 months of age and the level and distribution of human tau expression evaluated histologically (Fig. 1). Providing a point of reference for the pattern of expression, the level of human tau expression in various brain regions was compared with the commonly utilized rTg4510 mouse tauopathy model (14). As shown in Figure 1, similar to the rTg4510 model (Fig. 1c, f, m–r), a high level of human tau expression was observed in cortical and hippocampal regions in the AAV1-TauP301L model (Fig. 1b, e, g–l). Further increasing the utility of this model, human tau was also highly expressed in other areas of the brain including thalamic and midbrain regions (Fig. 1s–x), enabling the use of the AAV1-TauP301L model to evaluate genetic modifiers of non-cortical tauopathies. In addition, we evaluated human tau expression biochemically to provide an indication of the level of variability, and we observed minimal variation in human tau levels throughout the AAV1-TauP301L cohort (Supplementary Material, Fig. S1a). We also measured human tau levels by a quantitative immunoassay, which demonstrated that the average level of human tau in AAV1-TauP301L mice was 2.37 ± 0.087 ng/µg of brain tissue (mean ± SEM), which is significantly lower than rTg4510 mice that express ∼3.735 ± 0.057 ng/µg of human tau in the brain (Supplementary Material, Fig. S1b).Figure 1.


Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model.

Cook C, Kang SS, Carlomagno Y, Lin WL, Yue M, Kurti A, Shinohara M, Jansen-West K, Perkerson E, Castanedes-Casey M, Rousseau L, Phillips V, Bu G, Dickson DW, Petrucelli L, Fryer JD - Hum. Mol. Genet. (2015)

Widespread expression of human tau in AAV1-TauP301L model of tauopathy. Human tau-specific antibody (E1) reveals high level of expression throughout the brain and hippocampus in AAV1-TauP301L-injected (b and e) and rTg4510 mice (c and f), whereas AAV1-GFP-injected mice are negative (a and d). AAV1-TauP301L is also highly expressed throughout the hippocampal network (g–l), as well as other regions of the brain (s–x). The pattern of human tau expression in the hippocampal network (m–r) and other regions of the brain (y-dd) is shown in comparison with rTg4510 model. Scale bar in a–c equals 2 mm; scale bar in d–f equals 200 µm; scale bar in g–dd equals 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4599677&req=5

DDV336F1: Widespread expression of human tau in AAV1-TauP301L model of tauopathy. Human tau-specific antibody (E1) reveals high level of expression throughout the brain and hippocampus in AAV1-TauP301L-injected (b and e) and rTg4510 mice (c and f), whereas AAV1-GFP-injected mice are negative (a and d). AAV1-TauP301L is also highly expressed throughout the hippocampal network (g–l), as well as other regions of the brain (s–x). The pattern of human tau expression in the hippocampal network (m–r) and other regions of the brain (y-dd) is shown in comparison with rTg4510 model. Scale bar in a–c equals 2 mm; scale bar in d–f equals 200 µm; scale bar in g–dd equals 100 µm.
Mentions: To assess the ability to model tauopathy with somatic brain transgenesis with AAV1-TauP301L on postnatal day 0, mice were harvested at 6 months of age and the level and distribution of human tau expression evaluated histologically (Fig. 1). Providing a point of reference for the pattern of expression, the level of human tau expression in various brain regions was compared with the commonly utilized rTg4510 mouse tauopathy model (14). As shown in Figure 1, similar to the rTg4510 model (Fig. 1c, f, m–r), a high level of human tau expression was observed in cortical and hippocampal regions in the AAV1-TauP301L model (Fig. 1b, e, g–l). Further increasing the utility of this model, human tau was also highly expressed in other areas of the brain including thalamic and midbrain regions (Fig. 1s–x), enabling the use of the AAV1-TauP301L model to evaluate genetic modifiers of non-cortical tauopathies. In addition, we evaluated human tau expression biochemically to provide an indication of the level of variability, and we observed minimal variation in human tau levels throughout the AAV1-TauP301L cohort (Supplementary Material, Fig. S1a). We also measured human tau levels by a quantitative immunoassay, which demonstrated that the average level of human tau in AAV1-TauP301L mice was 2.37 ± 0.087 ng/µg of brain tissue (mean ± SEM), which is significantly lower than rTg4510 mice that express ∼3.735 ± 0.057 ng/µg of human tau in the brain (Supplementary Material, Fig. S1b).Figure 1.

Bottom Line: However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95.Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments.Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.

No MeSH data available.


Related in: MedlinePlus