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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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Protein levels of APP.SLA and Tau.P301L in hippocampal extracts.Biochemical analysis by western blotting of hippocampal extracts from AAV injected mice, as indicated. A: western blotting for total human and mouse APP with antibody B10/4 and for human APP with Mab WO2 on hippocampal extracts from AAV-APP.SLA injected mice at 1.5 weeks p.i. Quantitative data are from measurements with B10/4 following densitometric scanning (mean+/−SD; n = 3). B: western blotting for total human and mouse Tau with Mab Tau5 and for human Tau with Mab HT7 on hippocampal extracts from AAV-Tau.P301L injected mice at 1.5 weeks p.i. Quantitative data are from measurements with Tau5 following densitometric scanning (mean+/−SD; n = 3). C: western blotting reveals aggregated Tau oligomers in AAV-TauP301L mice. Protein extracts from AAV-Tau.P301L and AAV-EGFP injected mice (1.5 week p.i.) were separated on 8% Tris-Glycine gel under non-reducing and under reducing conditions. When blots were probed first with the secondary antibody only, non-specific bands denoted by asterisks were also revealed. Note the smears in the non-reduced samples (see text for details).
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pone-0007280-g004: Protein levels of APP.SLA and Tau.P301L in hippocampal extracts.Biochemical analysis by western blotting of hippocampal extracts from AAV injected mice, as indicated. A: western blotting for total human and mouse APP with antibody B10/4 and for human APP with Mab WO2 on hippocampal extracts from AAV-APP.SLA injected mice at 1.5 weeks p.i. Quantitative data are from measurements with B10/4 following densitometric scanning (mean+/−SD; n = 3). B: western blotting for total human and mouse Tau with Mab Tau5 and for human Tau with Mab HT7 on hippocampal extracts from AAV-Tau.P301L injected mice at 1.5 weeks p.i. Quantitative data are from measurements with Tau5 following densitometric scanning (mean+/−SD; n = 3). C: western blotting reveals aggregated Tau oligomers in AAV-TauP301L mice. Protein extracts from AAV-Tau.P301L and AAV-EGFP injected mice (1.5 week p.i.) were separated on 8% Tris-Glycine gel under non-reducing and under reducing conditions. When blots were probed first with the secondary antibody only, non-specific bands denoted by asterisks were also revealed. Note the smears in the non-reduced samples (see text for details).

Mentions: Western blotting of hippocampal protein extracts demonstrated relative levels of APP.SLA or Tau.P301L to be about two-fold higher than endogenous murine APP or murine protein tau, respectively (Figure 4A,B respectively). We conclude that neurodegeneration inflicted by Tau.P301L was not attributable to massive over-expression. Actually, pyramidal degeneration occurred at near-physiological levels of protein tau that were similar to those in our transgenic Tau.P301L mice [23], [24], which make the AAV models even more interesting.


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)

Protein levels of APP.SLA and Tau.P301L in hippocampal extracts.Biochemical analysis by western blotting of hippocampal extracts from AAV injected mice, as indicated. A: western blotting for total human and mouse APP with antibody B10/4 and for human APP with Mab WO2 on hippocampal extracts from AAV-APP.SLA injected mice at 1.5 weeks p.i. Quantitative data are from measurements with B10/4 following densitometric scanning (mean+/−SD; n = 3). B: western blotting for total human and mouse Tau with Mab Tau5 and for human Tau with Mab HT7 on hippocampal extracts from AAV-Tau.P301L injected mice at 1.5 weeks p.i. Quantitative data are from measurements with Tau5 following densitometric scanning (mean+/−SD; n = 3). C: western blotting reveals aggregated Tau oligomers in AAV-TauP301L mice. Protein extracts from AAV-Tau.P301L and AAV-EGFP injected mice (1.5 week p.i.) were separated on 8% Tris-Glycine gel under non-reducing and under reducing conditions. When blots were probed first with the secondary antibody only, non-specific bands denoted by asterisks were also revealed. Note the smears in the non-reduced samples (see text for details).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0007280-g004: Protein levels of APP.SLA and Tau.P301L in hippocampal extracts.Biochemical analysis by western blotting of hippocampal extracts from AAV injected mice, as indicated. A: western blotting for total human and mouse APP with antibody B10/4 and for human APP with Mab WO2 on hippocampal extracts from AAV-APP.SLA injected mice at 1.5 weeks p.i. Quantitative data are from measurements with B10/4 following densitometric scanning (mean+/−SD; n = 3). B: western blotting for total human and mouse Tau with Mab Tau5 and for human Tau with Mab HT7 on hippocampal extracts from AAV-Tau.P301L injected mice at 1.5 weeks p.i. Quantitative data are from measurements with Tau5 following densitometric scanning (mean+/−SD; n = 3). C: western blotting reveals aggregated Tau oligomers in AAV-TauP301L mice. Protein extracts from AAV-Tau.P301L and AAV-EGFP injected mice (1.5 week p.i.) were separated on 8% Tris-Glycine gel under non-reducing and under reducing conditions. When blots were probed first with the secondary antibody only, non-specific bands denoted by asterisks were also revealed. Note the smears in the non-reduced samples (see text for details).
Mentions: Western blotting of hippocampal protein extracts demonstrated relative levels of APP.SLA or Tau.P301L to be about two-fold higher than endogenous murine APP or murine protein tau, respectively (Figure 4A,B respectively). We conclude that neurodegeneration inflicted by Tau.P301L was not attributable to massive over-expression. Actually, pyramidal degeneration occurred at near-physiological levels of protein tau that were similar to those in our transgenic Tau.P301L mice [23], [24], which make the AAV models even more interesting.

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