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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

Tau filament formation in AAV1-TauP301L model of tauopathy. (a) Electron micrograph of a cortical neuron containing bundles of packed filaments that filled almost the entire cell body (N, nucleus). Arrow points to enlargement in (b) that shows the inclusion is not membrane-bound. (c) Further enlargement of (b) shows longitudinal, oblique and cross sections of filaments with diameters of 11–17 nm. Most of the filaments are straight. Some cross sections have a central lumen. Note the close proximity of filaments and mitochondria. (d) A filamentous aggregate excludes cytoplasmic organelles to its periphery. (e) Enlargement of the aggregate shows packed and loose filaments heavily labeled with E1 antibody that is specific for human tau. Scale bars are equal to 1 µm (a); 0.2 µm (b); 0.25 µm (d); 50 nm (c and e).
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DDV336F5: Tau filament formation in AAV1-TauP301L model of tauopathy. (a) Electron micrograph of a cortical neuron containing bundles of packed filaments that filled almost the entire cell body (N, nucleus). Arrow points to enlargement in (b) that shows the inclusion is not membrane-bound. (c) Further enlargement of (b) shows longitudinal, oblique and cross sections of filaments with diameters of 11–17 nm. Most of the filaments are straight. Some cross sections have a central lumen. Note the close proximity of filaments and mitochondria. (d) A filamentous aggregate excludes cytoplasmic organelles to its periphery. (e) Enlargement of the aggregate shows packed and loose filaments heavily labeled with E1 antibody that is specific for human tau. Scale bars are equal to 1 µm (a); 0.2 µm (b); 0.25 µm (d); 50 nm (c and e).

Mentions: Ultrastructural analysis of the AAV1-TauP301L model showed tau filaments in neuronal cytoplasmic inclusions that were not membrane-bound, as well as in both myelinated and unmyelinated cell processes (Figs. 5 and 6). Filaments were predominantly straight, with diameters of 11–17 nm (Fig. 5). A lumen was visible in some filaments in cross section, suggesting a tubule-like morphology. The packed filaments were oriented parallel to each other, and they excluded cytoplasmic organelles with the exception of mitochondria, which seemed to be aligned with and positioned in the same orientation as the filaments (Fig. 5a–c). Immuno-EM with an antibody specific for human tau (E1) verified these filaments were composed of human tau (Fig. 5d and e). Also noted was a range of deposition patterns, such as filamentous aggregates containing both tightly packed and loose filaments (Fig. 5d and e), or non-filamentous tau based upon strong immunolabeling with E1 antibody that was diffusely distributed throughout the cytoplasm, which may represent ‘pre-tangle’ pathology (Supplementary Material, Fig. S4a and b). E1 immunoreactivity was also detected in myelinated and unmyelinated cell processes, with the maturity of tau aggregates ranging from less-organized to well-formed filaments (Fig. 6a–e). Dystrophic neurites filled with dense, tightly compacted tau were also observed (Fig. 6f and g). Therefore, a very extensive range of pathology was detected in both the cell soma and processes in the AAV1-TauP301L model similar to that observed in human tauopathies.Figure 5.


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)

Tau filament formation in AAV1-TauP301L model of tauopathy. (a) Electron micrograph of a cortical neuron containing bundles of packed filaments that filled almost the entire cell body (N, nucleus). Arrow points to enlargement in (b) that shows the inclusion is not membrane-bound. (c) Further enlargement of (b) shows longitudinal, oblique and cross sections of filaments with diameters of 11–17 nm. Most of the filaments are straight. Some cross sections have a central lumen. Note the close proximity of filaments and mitochondria. (d) A filamentous aggregate excludes cytoplasmic organelles to its periphery. (e) Enlargement of the aggregate shows packed and loose filaments heavily labeled with E1 antibody that is specific for human tau. Scale bars are equal to 1 µm (a); 0.2 µm (b); 0.25 µm (d); 50 nm (c and e).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4599677&req=5

DDV336F5: Tau filament formation in AAV1-TauP301L model of tauopathy. (a) Electron micrograph of a cortical neuron containing bundles of packed filaments that filled almost the entire cell body (N, nucleus). Arrow points to enlargement in (b) that shows the inclusion is not membrane-bound. (c) Further enlargement of (b) shows longitudinal, oblique and cross sections of filaments with diameters of 11–17 nm. Most of the filaments are straight. Some cross sections have a central lumen. Note the close proximity of filaments and mitochondria. (d) A filamentous aggregate excludes cytoplasmic organelles to its periphery. (e) Enlargement of the aggregate shows packed and loose filaments heavily labeled with E1 antibody that is specific for human tau. Scale bars are equal to 1 µm (a); 0.2 µm (b); 0.25 µm (d); 50 nm (c and e).
Mentions: Ultrastructural analysis of the AAV1-TauP301L model showed tau filaments in neuronal cytoplasmic inclusions that were not membrane-bound, as well as in both myelinated and unmyelinated cell processes (Figs. 5 and 6). Filaments were predominantly straight, with diameters of 11–17 nm (Fig. 5). A lumen was visible in some filaments in cross section, suggesting a tubule-like morphology. The packed filaments were oriented parallel to each other, and they excluded cytoplasmic organelles with the exception of mitochondria, which seemed to be aligned with and positioned in the same orientation as the filaments (Fig. 5a–c). Immuno-EM with an antibody specific for human tau (E1) verified these filaments were composed of human tau (Fig. 5d and e). Also noted was a range of deposition patterns, such as filamentous aggregates containing both tightly packed and loose filaments (Fig. 5d and e), or non-filamentous tau based upon strong immunolabeling with E1 antibody that was diffusely distributed throughout the cytoplasm, which may represent ‘pre-tangle’ pathology (Supplementary Material, Fig. S4a and b). E1 immunoreactivity was also detected in myelinated and unmyelinated cell processes, with the maturity of tau aggregates ranging from less-organized to well-formed filaments (Fig. 6a–e). Dystrophic neurites filled with dense, tightly compacted tau were also observed (Fig. 6f and g). Therefore, a very extensive range of pathology was detected in both the cell soma and processes in the AAV1-TauP301L model similar to that observed in human tauopathies.Figure 5.

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