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AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice.

Jaworski T, Dewachter I, Lechat B, Croes S, Termont A, Demedts D, Borghgraef P, Devijver H, Filipkowski RK, Kaczmarek L, Kügler S, Van Leuven F - PLoS ONE (2009)

Bottom Line: In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks.Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo.The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Experimental Genetics Group, Department of Human Genetics, KULeuven-Campus, Leuven, Belgium.

ABSTRACT
In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

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Related in: MedlinePlus

Tau-mediated neurodegeneration relates to cell cycle.A: IHC for indicated markers in brain of wild-type mice injected with 10E8 t.u. AAV-Tau.P301L analyzed 3 weeks p.i. comparing injected (left panels) to non-injected (right panels) hemispheres. Note the predominant nuclear localization of cyclinB1 and cytoplasmic expression of cyclinD2 as well as the strong phosphorylation of Retinoblastoma protein. Marker PCNA was typical for a subset of neurons in a different stage of degeneration. Scale bars 30 µm. B: IHC for active members of MAPK family: phospho-SAPK/JNK, phospho-p44/42 MAPK, phospho-p38 MAPK. Compared injected (left) to non-injected (right) hemispheres. Scale bars 30 µm. C: CyclinD2 deficient mice were injected with 10E8 t.u. AAV-Tau.P301L and analyzed 3 weeks p.i. compared to wild-type littermates (n = 4 each) by IHC for total human tau with HT7 (lower panel; scale bar 100 µm) and for NeuN as marker for neuronal nuclei (upper panel; scale bars 1 mm). Note the similar level of neurodegeneration in wild-type and CyclinD2 deficient mice injected with AAV-Tau.P301L.
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pone-0007280-g008: Tau-mediated neurodegeneration relates to cell cycle.A: IHC for indicated markers in brain of wild-type mice injected with 10E8 t.u. AAV-Tau.P301L analyzed 3 weeks p.i. comparing injected (left panels) to non-injected (right panels) hemispheres. Note the predominant nuclear localization of cyclinB1 and cytoplasmic expression of cyclinD2 as well as the strong phosphorylation of Retinoblastoma protein. Marker PCNA was typical for a subset of neurons in a different stage of degeneration. Scale bars 30 µm. B: IHC for active members of MAPK family: phospho-SAPK/JNK, phospho-p44/42 MAPK, phospho-p38 MAPK. Compared injected (left) to non-injected (right) hemispheres. Scale bars 30 µm. C: CyclinD2 deficient mice were injected with 10E8 t.u. AAV-Tau.P301L and analyzed 3 weeks p.i. compared to wild-type littermates (n = 4 each) by IHC for total human tau with HT7 (lower panel; scale bar 100 µm) and for NeuN as marker for neuronal nuclei (upper panel; scale bars 1 mm). Note the similar level of neurodegeneration in wild-type and CyclinD2 deficient mice injected with AAV-Tau.P301L.

Mentions: Among cell-cycle and related markers, cyclinD2 and cyclinB1 were strongly up-regulated 3 weeks p.i. in degenerating neurons in AAV-Tau mice (Figure 8A) corroborated by other markers, e.g. PCNA and phosphorylated retinoblastoma protein (Figure 8A). Conversely, cell-cycle inhibitor p27KIP1 was strongly down-regulated, while markers like Ki67 and cdk2 were hardly affected by tau-mediated neurodegeneration (Figure 8A; results not shown). Effects on these and other markers were restricted to sub-regions and/or sub-sets of neurons in AAV-Tau mice, while most were unaffected in AAV-EGFP or AAV-APP.SLA injected mice (results not shown).


AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice.

Jaworski T, Dewachter I, Lechat B, Croes S, Termont A, Demedts D, Borghgraef P, Devijver H, Filipkowski RK, Kaczmarek L, Kügler S, Van Leuven F - PLoS ONE (2009)

Tau-mediated neurodegeneration relates to cell cycle.A: IHC for indicated markers in brain of wild-type mice injected with 10E8 t.u. AAV-Tau.P301L analyzed 3 weeks p.i. comparing injected (left panels) to non-injected (right panels) hemispheres. Note the predominant nuclear localization of cyclinB1 and cytoplasmic expression of cyclinD2 as well as the strong phosphorylation of Retinoblastoma protein. Marker PCNA was typical for a subset of neurons in a different stage of degeneration. Scale bars 30 µm. B: IHC for active members of MAPK family: phospho-SAPK/JNK, phospho-p44/42 MAPK, phospho-p38 MAPK. Compared injected (left) to non-injected (right) hemispheres. Scale bars 30 µm. C: CyclinD2 deficient mice were injected with 10E8 t.u. AAV-Tau.P301L and analyzed 3 weeks p.i. compared to wild-type littermates (n = 4 each) by IHC for total human tau with HT7 (lower panel; scale bar 100 µm) and for NeuN as marker for neuronal nuclei (upper panel; scale bars 1 mm). Note the similar level of neurodegeneration in wild-type and CyclinD2 deficient mice injected with AAV-Tau.P301L.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2748684&req=5

pone-0007280-g008: Tau-mediated neurodegeneration relates to cell cycle.A: IHC for indicated markers in brain of wild-type mice injected with 10E8 t.u. AAV-Tau.P301L analyzed 3 weeks p.i. comparing injected (left panels) to non-injected (right panels) hemispheres. Note the predominant nuclear localization of cyclinB1 and cytoplasmic expression of cyclinD2 as well as the strong phosphorylation of Retinoblastoma protein. Marker PCNA was typical for a subset of neurons in a different stage of degeneration. Scale bars 30 µm. B: IHC for active members of MAPK family: phospho-SAPK/JNK, phospho-p44/42 MAPK, phospho-p38 MAPK. Compared injected (left) to non-injected (right) hemispheres. Scale bars 30 µm. C: CyclinD2 deficient mice were injected with 10E8 t.u. AAV-Tau.P301L and analyzed 3 weeks p.i. compared to wild-type littermates (n = 4 each) by IHC for total human tau with HT7 (lower panel; scale bar 100 µm) and for NeuN as marker for neuronal nuclei (upper panel; scale bars 1 mm). Note the similar level of neurodegeneration in wild-type and CyclinD2 deficient mice injected with AAV-Tau.P301L.
Mentions: Among cell-cycle and related markers, cyclinD2 and cyclinB1 were strongly up-regulated 3 weeks p.i. in degenerating neurons in AAV-Tau mice (Figure 8A) corroborated by other markers, e.g. PCNA and phosphorylated retinoblastoma protein (Figure 8A). Conversely, cell-cycle inhibitor p27KIP1 was strongly down-regulated, while markers like Ki67 and cdk2 were hardly affected by tau-mediated neurodegeneration (Figure 8A; results not shown). Effects on these and other markers were restricted to sub-regions and/or sub-sets of neurons in AAV-Tau mice, while most were unaffected in AAV-EGFP or AAV-APP.SLA injected mice (results not shown).

Bottom Line: In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks.Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo.The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Experimental Genetics Group, Department of Human Genetics, KULeuven-Campus, Leuven, Belgium.

ABSTRACT
In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

Show MeSH
Related in: MedlinePlus