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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

Aberrant proteolysis of PSD-95 in AAV1-TauP301L mice. (a) Accumulation of a 50-kDa PSD95 fragment was observed in mice injected with AAV1-TauP301L, whereas the levels of full-length PSD95 were unchanged. (b) Quantification of the 50-kDa fragment normalized to full-length PSD95 revealed a highly significant increase in AAV1-TauP301L mice (t = 7.47, P < 0.0001). (c) The 50-kDa/full-length PSD95 ratio is significantly correlated with the levels of human tau in animals injected with AAV1-TauP301L (r = 0.74, P = 0.0008). ***P < 0.0001.
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DDV336F9: Aberrant proteolysis of PSD-95 in AAV1-TauP301L mice. (a) Accumulation of a 50-kDa PSD95 fragment was observed in mice injected with AAV1-TauP301L, whereas the levels of full-length PSD95 were unchanged. (b) Quantification of the 50-kDa fragment normalized to full-length PSD95 revealed a highly significant increase in AAV1-TauP301L mice (t = 7.47, P < 0.0001). (c) The 50-kDa/full-length PSD95 ratio is significantly correlated with the levels of human tau in animals injected with AAV1-TauP301L (r = 0.74, P = 0.0008). ***P < 0.0001.

Mentions: To determine the behavioral impact of AAV1-TauP301L-driven pathology, we evaluated performance on tasks designed to assess exploration, anxiety, as well as learning and memory that are often characteristically abnormal in various human tauopathies. In the open-field assay (OFA), AAV1-TauP301L mice exhibited hyperactivity as assessed by total distance traveled and time spent mobile (Fig. 8a and b). In addition to hyperactivity, AAV1-TauP301L mice also displayed a decreased tendency to explore the center of the open field (Fig. 8c), which is typically characteristic of increased anxiety. However, in the elevated plus maze (EPM), AAV1-TauP301L mice actually spent a greater amount of time in the open arms (Fig. 8d), indicating that this model is characterized by aberrant exploratory behavior and disinhibition, similar to the results obtained in the rTg4510 transgenic mouse model (40). AAV1-TauP301L mice also exhibited deficits in a contextual fear conditioning paradigm, with significant memory impairments in their ability to associate either the context (Fig. 8e) or an auditory cue (Fig. 8f), reflective of hippocampal and amygdala dysfunction. As similar behavioral abnormalities have been noted in rTg4510 mice (40), as well as other models of tauopathy (41–46), the utilization of somatic brain transgenesis to deliver AAV1-TauP301L to neonatal mice recapitulates several key features characteristic of tauopathy but in the absence of overt neuronal loss. Therefore, to determine whether synaptic abnormalities were present in AAV1-TauP301L mice, we evaluated the expression of the postsynaptic scaffolding protein, PSD95. While the levels of full-length PSD95 were unaltered (Fig. 9a, t = 0.41, P = 0.69), we observed the appearance and significant accumulation of a 50-kDa fragment in all AAV1-TauP301L mice (Fig. 9a and b, t = 7.47, P < 0.0001), a fragment that has previously been reported to be generated by calpain under conditions of excitotoxicity and ischemia/reperfusion injury (47,48). We also confirmed that human tau expression was positively correlated with the levels of the 50-kDa PSD95 fragment (Fig. 9c, r = 0.74, P = 0.0008), suggesting that the aberrant processing of PSD95 is a result of AAV1-TauP301L expression.Figure 8.


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)

Aberrant proteolysis of PSD-95 in AAV1-TauP301L mice. (a) Accumulation of a 50-kDa PSD95 fragment was observed in mice injected with AAV1-TauP301L, whereas the levels of full-length PSD95 were unchanged. (b) Quantification of the 50-kDa fragment normalized to full-length PSD95 revealed a highly significant increase in AAV1-TauP301L mice (t = 7.47, P < 0.0001). (c) The 50-kDa/full-length PSD95 ratio is significantly correlated with the levels of human tau in animals injected with AAV1-TauP301L (r = 0.74, P = 0.0008). ***P < 0.0001.
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Related In: Results  -  Collection

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DDV336F9: Aberrant proteolysis of PSD-95 in AAV1-TauP301L mice. (a) Accumulation of a 50-kDa PSD95 fragment was observed in mice injected with AAV1-TauP301L, whereas the levels of full-length PSD95 were unchanged. (b) Quantification of the 50-kDa fragment normalized to full-length PSD95 revealed a highly significant increase in AAV1-TauP301L mice (t = 7.47, P < 0.0001). (c) The 50-kDa/full-length PSD95 ratio is significantly correlated with the levels of human tau in animals injected with AAV1-TauP301L (r = 0.74, P = 0.0008). ***P < 0.0001.
Mentions: To determine the behavioral impact of AAV1-TauP301L-driven pathology, we evaluated performance on tasks designed to assess exploration, anxiety, as well as learning and memory that are often characteristically abnormal in various human tauopathies. In the open-field assay (OFA), AAV1-TauP301L mice exhibited hyperactivity as assessed by total distance traveled and time spent mobile (Fig. 8a and b). In addition to hyperactivity, AAV1-TauP301L mice also displayed a decreased tendency to explore the center of the open field (Fig. 8c), which is typically characteristic of increased anxiety. However, in the elevated plus maze (EPM), AAV1-TauP301L mice actually spent a greater amount of time in the open arms (Fig. 8d), indicating that this model is characterized by aberrant exploratory behavior and disinhibition, similar to the results obtained in the rTg4510 transgenic mouse model (40). AAV1-TauP301L mice also exhibited deficits in a contextual fear conditioning paradigm, with significant memory impairments in their ability to associate either the context (Fig. 8e) or an auditory cue (Fig. 8f), reflective of hippocampal and amygdala dysfunction. As similar behavioral abnormalities have been noted in rTg4510 mice (40), as well as other models of tauopathy (41–46), the utilization of somatic brain transgenesis to deliver AAV1-TauP301L to neonatal mice recapitulates several key features characteristic of tauopathy but in the absence of overt neuronal loss. Therefore, to determine whether synaptic abnormalities were present in AAV1-TauP301L mice, we evaluated the expression of the postsynaptic scaffolding protein, PSD95. While the levels of full-length PSD95 were unaltered (Fig. 9a, t = 0.41, P = 0.69), we observed the appearance and significant accumulation of a 50-kDa fragment in all AAV1-TauP301L mice (Fig. 9a and b, t = 7.47, P < 0.0001), a fragment that has previously been reported to be generated by calpain under conditions of excitotoxicity and ischemia/reperfusion injury (47,48). We also confirmed that human tau expression was positively correlated with the levels of the 50-kDa PSD95 fragment (Fig. 9c, r = 0.74, P = 0.0008), suggesting that the aberrant processing of PSD95 is a result of AAV1-TauP301L expression.Figure 8.

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