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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

Deposition of abnormally folded and protease-resistant tau. (a and b) Injection of AAV1-TauP301L leads to the accumulation of tau positive for MC1, a well-characterized marker of abnormally folded tau, as well as proteinase K-resistant tau that is positive for Ab39, a marker of mature NFTs. Representative images from the CA1 field of the hippocampus (a) and cortex (b). Scale bar is equal to 100 µm.
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DDV336F3: Deposition of abnormally folded and protease-resistant tau. (a and b) Injection of AAV1-TauP301L leads to the accumulation of tau positive for MC1, a well-characterized marker of abnormally folded tau, as well as proteinase K-resistant tau that is positive for Ab39, a marker of mature NFTs. Representative images from the CA1 field of the hippocampus (a) and cortex (b). Scale bar is equal to 100 µm.

Mentions: In order to further characterize the pathology in AAV1-TauP301L-injected animals, we evaluated immunoreactivity for well-known markers of abnormal conformational changes in the tau protein. The MC1 antibody, which detects a conformational change that occurs early in NFT formation (15,16), labeled inclusions in the hippocampus and cortex (Fig. 3a and b) as well as other brain regions of AAV1-TauP301L mice (data not shown). To detect mature NFT pathology, we pretreated tissue sections with proteinase K and subsequently stained with the conformational-dependent antibody Ab39 (17–19). The strong positivity for Ab39 in hippocampal and cortical regions (Fig. 3a and b) was indicative of the formation of a mature, protease-resistant form of neurofibrillary pathology. In addition, inclusions in AAV1-TauP301L mice were also positive on Gallyas silver stain and Thioflavin S fluorescent microscopy (Fig. 4), denoting argyrophilic lesions (20) and the adoption of β-pleated sheet structure (21), respectively. These findings suggest that a wide range of pathology at varying stages of maturity is observed in the AAV1-TauP301L model, which models changes observed in human tauopathies. We also quantified the number of NeuN-positive nuclei (Supplementary Material, Fig. S2) but detected no significant difference between AAV1-GFP and AAV1-TauP301L mice (t = 1.4, P = 0.2), indicating that the deposition of pathological forms of tau was not accompanied by significant neuronal loss in this model at 6 months of age.Figure 3.


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)

Deposition of abnormally folded and protease-resistant tau. (a and b) Injection of AAV1-TauP301L leads to the accumulation of tau positive for MC1, a well-characterized marker of abnormally folded tau, as well as proteinase K-resistant tau that is positive for Ab39, a marker of mature NFTs. Representative images from the CA1 field of the hippocampus (a) and cortex (b). Scale bar is equal to 100 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV336F3: Deposition of abnormally folded and protease-resistant tau. (a and b) Injection of AAV1-TauP301L leads to the accumulation of tau positive for MC1, a well-characterized marker of abnormally folded tau, as well as proteinase K-resistant tau that is positive for Ab39, a marker of mature NFTs. Representative images from the CA1 field of the hippocampus (a) and cortex (b). Scale bar is equal to 100 µm.
Mentions: In order to further characterize the pathology in AAV1-TauP301L-injected animals, we evaluated immunoreactivity for well-known markers of abnormal conformational changes in the tau protein. The MC1 antibody, which detects a conformational change that occurs early in NFT formation (15,16), labeled inclusions in the hippocampus and cortex (Fig. 3a and b) as well as other brain regions of AAV1-TauP301L mice (data not shown). To detect mature NFT pathology, we pretreated tissue sections with proteinase K and subsequently stained with the conformational-dependent antibody Ab39 (17–19). The strong positivity for Ab39 in hippocampal and cortical regions (Fig. 3a and b) was indicative of the formation of a mature, protease-resistant form of neurofibrillary pathology. In addition, inclusions in AAV1-TauP301L mice were also positive on Gallyas silver stain and Thioflavin S fluorescent microscopy (Fig. 4), denoting argyrophilic lesions (20) and the adoption of β-pleated sheet structure (21), respectively. These findings suggest that a wide range of pathology at varying stages of maturity is observed in the AAV1-TauP301L model, which models changes observed in human tauopathies. We also quantified the number of NeuN-positive nuclei (Supplementary Material, Fig. S2) but detected no significant difference between AAV1-GFP and AAV1-TauP301L mice (t = 1.4, P = 0.2), indicating that the deposition of pathological forms of tau was not accompanied by significant neuronal loss in this model at 6 months of age.Figure 3.

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