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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

Accumulation of hyperphosphorylated tau species in AAV-driven model of tauopathy. (a and b) Representative images depicting the deposition of PHF1- and CP13-positive tau species in the CA1 field of the hippocampus (a), as well as the cortex (b). (c) Mice injected with AAV1-TauP301L express 4-fold higher tau levels in the forebrain as assessed by Tau 5 (recognizing both mouse and human tau), leading to accumulation of tau that is hyperphosphorylated on multiple epitopes. (d) Quantification of PHF1 normalized to GAPDH (t = 3.46, P = 0.0018); (e) CP13 (t = 6.26, P < 0.0001); (f) 12E8 (t = 7, P < 0.0001); (g) Tau 5 (t = 7.45, P < 0.0001). Scale bar is equal to 100 µm.
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DDV336F2: Accumulation of hyperphosphorylated tau species in AAV-driven model of tauopathy. (a and b) Representative images depicting the deposition of PHF1- and CP13-positive tau species in the CA1 field of the hippocampus (a), as well as the cortex (b). (c) Mice injected with AAV1-TauP301L express 4-fold higher tau levels in the forebrain as assessed by Tau 5 (recognizing both mouse and human tau), leading to accumulation of tau that is hyperphosphorylated on multiple epitopes. (d) Quantification of PHF1 normalized to GAPDH (t = 3.46, P = 0.0018); (e) CP13 (t = 6.26, P < 0.0001); (f) 12E8 (t = 7, P < 0.0001); (g) Tau 5 (t = 7.45, P < 0.0001). Scale bar is equal to 100 µm.

Mentions: Given that neurofibrillary tangles (NFTs) contain tau species that are abnormally hyperphosphorylated on multiple epitopes, we wanted to determine the degree of tau hyperphosphorylation as well as the level of tau overexpression relative to endogenous tau in the AAV1-TauP301L model (Fig. 2). Strong immunoreactivity for the phospho-tau-specific antibodies PHF1 (pS396/404) and CP13 (pS202) was observed in hippocampal (Fig. 2a) and cortical (Fig. 2b) regions, in addition to other brain regions (data not shown), indicative of pathological changes in the tau protein. Total tau levels were evaluated biochemically using Tau 5 (Fig. 2c and g), which detects both mouse and human tau independently of phosphorylation state. This analysis revealed that while total tau levels were elevated by approximately 4-fold in AAV1-TauP301L mice (Fig. 2g), the abnormal phosphorylation of tau at the 12E8 epitope (pS262/356) was increased by more than 20-fold (Fig. 2c and f), most likely due to the very low level of phosphorylation at this pathologically relevant epitope under normal conditions.Figure 2.


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)

Accumulation of hyperphosphorylated tau species in AAV-driven model of tauopathy. (a and b) Representative images depicting the deposition of PHF1- and CP13-positive tau species in the CA1 field of the hippocampus (a), as well as the cortex (b). (c) Mice injected with AAV1-TauP301L express 4-fold higher tau levels in the forebrain as assessed by Tau 5 (recognizing both mouse and human tau), leading to accumulation of tau that is hyperphosphorylated on multiple epitopes. (d) Quantification of PHF1 normalized to GAPDH (t = 3.46, P = 0.0018); (e) CP13 (t = 6.26, P < 0.0001); (f) 12E8 (t = 7, P < 0.0001); (g) Tau 5 (t = 7.45, P < 0.0001). Scale bar is equal to 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4599677&req=5

DDV336F2: Accumulation of hyperphosphorylated tau species in AAV-driven model of tauopathy. (a and b) Representative images depicting the deposition of PHF1- and CP13-positive tau species in the CA1 field of the hippocampus (a), as well as the cortex (b). (c) Mice injected with AAV1-TauP301L express 4-fold higher tau levels in the forebrain as assessed by Tau 5 (recognizing both mouse and human tau), leading to accumulation of tau that is hyperphosphorylated on multiple epitopes. (d) Quantification of PHF1 normalized to GAPDH (t = 3.46, P = 0.0018); (e) CP13 (t = 6.26, P < 0.0001); (f) 12E8 (t = 7, P < 0.0001); (g) Tau 5 (t = 7.45, P < 0.0001). Scale bar is equal to 100 µm.
Mentions: Given that neurofibrillary tangles (NFTs) contain tau species that are abnormally hyperphosphorylated on multiple epitopes, we wanted to determine the degree of tau hyperphosphorylation as well as the level of tau overexpression relative to endogenous tau in the AAV1-TauP301L model (Fig. 2). Strong immunoreactivity for the phospho-tau-specific antibodies PHF1 (pS396/404) and CP13 (pS202) was observed in hippocampal (Fig. 2a) and cortical (Fig. 2b) regions, in addition to other brain regions (data not shown), indicative of pathological changes in the tau protein. Total tau levels were evaluated biochemically using Tau 5 (Fig. 2c and g), which detects both mouse and human tau independently of phosphorylation state. This analysis revealed that while total tau levels were elevated by approximately 4-fold in AAV1-TauP301L mice (Fig. 2g), the abnormal phosphorylation of tau at the 12E8 epitope (pS262/356) was increased by more than 20-fold (Fig. 2c and f), most likely due to the very low level of phosphorylation at this pathologically relevant epitope under normal conditions.Figure 2.

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