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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 pathology is associated with robust gliosis and inflammation. (a and b) Microgliosis and astrocytosis detected by Iba1 and GFAP, respectively, in the CA1 field of the hippocampus (a) and cortical regions (b). (c–g) Inflammatory markers were evaluated by RT-qPCR. (c) Aif1 (t = 5.3, P < 0.0001), (d) Gfap (t = 2.5, P = 0.017), (e) Il1b (t = 3.15, P = 0.004), (f) Il6 (t = 3.17, P = 0.004) and (g) Tnfa (t = 2.9, P = 0.007) were all significantly elevated in AAV1-TauP301L mice compared with AAV1-GFP controls. Scale bar is equal to 100 µm *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001.
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DDV336F7: Tau pathology is associated with robust gliosis and inflammation. (a and b) Microgliosis and astrocytosis detected by Iba1 and GFAP, respectively, in the CA1 field of the hippocampus (a) and cortical regions (b). (c–g) Inflammatory markers were evaluated by RT-qPCR. (c) Aif1 (t = 5.3, P < 0.0001), (d) Gfap (t = 2.5, P = 0.017), (e) Il1b (t = 3.15, P = 0.004), (f) Il6 (t = 3.17, P = 0.004) and (g) Tnfa (t = 2.9, P = 0.007) were all significantly elevated in AAV1-TauP301L mice compared with AAV1-GFP controls. Scale bar is equal to 100 µm *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001.

Mentions: Several lines of evidence indicate that increasing inflammation exacerbates tau pathology (24–27). Moreover, tau pathology is associated with inflammation in both human tissue (28–30) and animal models (24,31,32), suggesting that a toxic interplay between neuroinflammation and tau pathology regulates disease progression. To evaluate whether inflammation was observed in animals injected with AAV1-TauP301L, we first examined glial activation histologically. The intensity of immunolabeling in addition to the morphology of IBA1-positive microglia was markedly altered in the hippocampus and cortex of mice injected with AAV1-TauP301L, indicative of microglial activation (Fig. 7a and b). Elevated expression and altered morphology of GFAP-positive astrocytes was also noted in the same brain regions (Fig. 7a and b), demonstrating that the presence of tau pathology is associated with both microgliosis and astrocytosis in this model. To further investigate the inflammatory changes driven by AAV1-TauP301L expression, we utilized RT-qPCR to measure mRNA levels and identified a significant upregulation in Aif1 (encoding Iba1) and Gfap transcripts, as well as the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α (Fig. 7c–g). Intriguingly, these same pro-inflammatory cytokines have also been reported to be elevated in plasma, cerebrospinal fluid and brain from patients with AD or mild cognitive impairment (33–39), further supporting the pathological relevance of the AAV1-TauP301L model.Figure 7.


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 pathology is associated with robust gliosis and inflammation. (a and b) Microgliosis and astrocytosis detected by Iba1 and GFAP, respectively, in the CA1 field of the hippocampus (a) and cortical regions (b). (c–g) Inflammatory markers were evaluated by RT-qPCR. (c) Aif1 (t = 5.3, P < 0.0001), (d) Gfap (t = 2.5, P = 0.017), (e) Il1b (t = 3.15, P = 0.004), (f) Il6 (t = 3.17, P = 0.004) and (g) Tnfa (t = 2.9, P = 0.007) were all significantly elevated in AAV1-TauP301L mice compared with AAV1-GFP controls. Scale bar is equal to 100 µm *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001.
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Related In: Results  -  Collection

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DDV336F7: Tau pathology is associated with robust gliosis and inflammation. (a and b) Microgliosis and astrocytosis detected by Iba1 and GFAP, respectively, in the CA1 field of the hippocampus (a) and cortical regions (b). (c–g) Inflammatory markers were evaluated by RT-qPCR. (c) Aif1 (t = 5.3, P < 0.0001), (d) Gfap (t = 2.5, P = 0.017), (e) Il1b (t = 3.15, P = 0.004), (f) Il6 (t = 3.17, P = 0.004) and (g) Tnfa (t = 2.9, P = 0.007) were all significantly elevated in AAV1-TauP301L mice compared with AAV1-GFP controls. Scale bar is equal to 100 µm *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001.
Mentions: Several lines of evidence indicate that increasing inflammation exacerbates tau pathology (24–27). Moreover, tau pathology is associated with inflammation in both human tissue (28–30) and animal models (24,31,32), suggesting that a toxic interplay between neuroinflammation and tau pathology regulates disease progression. To evaluate whether inflammation was observed in animals injected with AAV1-TauP301L, we first examined glial activation histologically. The intensity of immunolabeling in addition to the morphology of IBA1-positive microglia was markedly altered in the hippocampus and cortex of mice injected with AAV1-TauP301L, indicative of microglial activation (Fig. 7a and b). Elevated expression and altered morphology of GFAP-positive astrocytes was also noted in the same brain regions (Fig. 7a and b), demonstrating that the presence of tau pathology is associated with both microgliosis and astrocytosis in this model. To further investigate the inflammatory changes driven by AAV1-TauP301L expression, we utilized RT-qPCR to measure mRNA levels and identified a significant upregulation in Aif1 (encoding Iba1) and Gfap transcripts, as well as the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α (Fig. 7c–g). Intriguingly, these same pro-inflammatory cytokines have also been reported to be elevated in plasma, cerebrospinal fluid and brain from patients with AD or mild cognitive impairment (33–39), further supporting the pathological relevance of the AAV1-TauP301L model.Figure 7.

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