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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

Dose-dependence and time-line of AAV-Tau.P301L mediated neurodegeneration.A. Intracerebral injection of AAV-Tau.P301L at doses indicated in wild-type mice (n = 3 per dose) analyzed at 4 weeks p.i. by IHC for total human Tau with HT7 and counterstained with hematoxylin (upper panels). IHC for NeuN visualized neuronal nuclei without counterstaining (lower panels). Scale bar 0.5 mm. Note thinning of CA1/2 already with lowest dose of APP-Tau.P301L. B. Time line of AAV-Tau.P301L mediated neurodegeneration. Intracerebral injection of 10E8 t.u. of AAV-Tau.P301L in wild-type mice analyzed at 1.5 weeks (n = 4), 3 weeks (n = 6), 6 weeks (n = 6), 9 weeks (n = 6) and 12 weeks (n = 6) p.i.. Control mice were intracerebrally injected with AAV-EGFP (10E8 t.u.) sacrificed at same time-points p.i. (all n = 4). Analysis by IHC with HT7 for total human tau, NeuN for neuronal nuclei, GFAP for astroglia and MHCII for activated microglia as indicated above the panels (scale bars 1 mm). Histological staining with FluoroJadeB for degenerating neurons and activated glia (see text for details) (scale bar 0.1 mm). Note that expression of human Tau is highest at 1.5 week p.i. and subsides later, paralleling the loss of NeuN immunoreactivity. The FJB signals in CA1 mark degenerating pyramidal neurons at 3 weeks p.i. but changes to an astroglial pattern at later time-points (see text for details). Note that at 3 weeks p.i. the loss of neurons and FJB positive signals in CA concurs with intense microgliosis, which subsides completely at 12 weeks p.i. while astrogliosis is much less specific in time and spatial distribution (see text for details).
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pone-0007280-g003: Dose-dependence and time-line of AAV-Tau.P301L mediated neurodegeneration.A. Intracerebral injection of AAV-Tau.P301L at doses indicated in wild-type mice (n = 3 per dose) analyzed at 4 weeks p.i. by IHC for total human Tau with HT7 and counterstained with hematoxylin (upper panels). IHC for NeuN visualized neuronal nuclei without counterstaining (lower panels). Scale bar 0.5 mm. Note thinning of CA1/2 already with lowest dose of APP-Tau.P301L. B. Time line of AAV-Tau.P301L mediated neurodegeneration. Intracerebral injection of 10E8 t.u. of AAV-Tau.P301L in wild-type mice analyzed at 1.5 weeks (n = 4), 3 weeks (n = 6), 6 weeks (n = 6), 9 weeks (n = 6) and 12 weeks (n = 6) p.i.. Control mice were intracerebrally injected with AAV-EGFP (10E8 t.u.) sacrificed at same time-points p.i. (all n = 4). Analysis by IHC with HT7 for total human tau, NeuN for neuronal nuclei, GFAP for astroglia and MHCII for activated microglia as indicated above the panels (scale bars 1 mm). Histological staining with FluoroJadeB for degenerating neurons and activated glia (see text for details) (scale bar 0.1 mm). Note that expression of human Tau is highest at 1.5 week p.i. and subsides later, paralleling the loss of NeuN immunoreactivity. The FJB signals in CA1 mark degenerating pyramidal neurons at 3 weeks p.i. but changes to an astroglial pattern at later time-points (see text for details). Note that at 3 weeks p.i. the loss of neurons and FJB positive signals in CA concurs with intense microgliosis, which subsides completely at 12 weeks p.i. while astrogliosis is much less specific in time and spatial distribution (see text for details).

Mentions: In sharp contrast, the intracerebral injection of AAV-Tau.P301L presented at first a very surprising outcome at 12 weeks p.i., because expression of human tau was detected in cortex but was hardly detectable in the hippocampus, i.e. where the virus was injected (Figure 2 A–C). Counterstaining for nuclei and in depth analysis resolved the apparent contradiction: expression of human protein Tau was low in pyramidal neurons in the hippocampus because of the nearly complete loss of pyramidal neurons in CA1/2 (Figure 2 A–C; compare injected to contra-lateral hemisphere). The dramatic nearly complete elimination of pyramidal CA neurons was confirmed by Nissl staining (data not shown) and by IHC for NeuN as marker for neuronal nuclei (Figure 3A, lower panels).


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)

Dose-dependence and time-line of AAV-Tau.P301L mediated neurodegeneration.A. Intracerebral injection of AAV-Tau.P301L at doses indicated in wild-type mice (n = 3 per dose) analyzed at 4 weeks p.i. by IHC for total human Tau with HT7 and counterstained with hematoxylin (upper panels). IHC for NeuN visualized neuronal nuclei without counterstaining (lower panels). Scale bar 0.5 mm. Note thinning of CA1/2 already with lowest dose of APP-Tau.P301L. B. Time line of AAV-Tau.P301L mediated neurodegeneration. Intracerebral injection of 10E8 t.u. of AAV-Tau.P301L in wild-type mice analyzed at 1.5 weeks (n = 4), 3 weeks (n = 6), 6 weeks (n = 6), 9 weeks (n = 6) and 12 weeks (n = 6) p.i.. Control mice were intracerebrally injected with AAV-EGFP (10E8 t.u.) sacrificed at same time-points p.i. (all n = 4). Analysis by IHC with HT7 for total human tau, NeuN for neuronal nuclei, GFAP for astroglia and MHCII for activated microglia as indicated above the panels (scale bars 1 mm). Histological staining with FluoroJadeB for degenerating neurons and activated glia (see text for details) (scale bar 0.1 mm). Note that expression of human Tau is highest at 1.5 week p.i. and subsides later, paralleling the loss of NeuN immunoreactivity. The FJB signals in CA1 mark degenerating pyramidal neurons at 3 weeks p.i. but changes to an astroglial pattern at later time-points (see text for details). Note that at 3 weeks p.i. the loss of neurons and FJB positive signals in CA concurs with intense microgliosis, which subsides completely at 12 weeks p.i. while astrogliosis is much less specific in time and spatial distribution (see text for details).
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Related In: Results  -  Collection

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

pone-0007280-g003: Dose-dependence and time-line of AAV-Tau.P301L mediated neurodegeneration.A. Intracerebral injection of AAV-Tau.P301L at doses indicated in wild-type mice (n = 3 per dose) analyzed at 4 weeks p.i. by IHC for total human Tau with HT7 and counterstained with hematoxylin (upper panels). IHC for NeuN visualized neuronal nuclei without counterstaining (lower panels). Scale bar 0.5 mm. Note thinning of CA1/2 already with lowest dose of APP-Tau.P301L. B. Time line of AAV-Tau.P301L mediated neurodegeneration. Intracerebral injection of 10E8 t.u. of AAV-Tau.P301L in wild-type mice analyzed at 1.5 weeks (n = 4), 3 weeks (n = 6), 6 weeks (n = 6), 9 weeks (n = 6) and 12 weeks (n = 6) p.i.. Control mice were intracerebrally injected with AAV-EGFP (10E8 t.u.) sacrificed at same time-points p.i. (all n = 4). Analysis by IHC with HT7 for total human tau, NeuN for neuronal nuclei, GFAP for astroglia and MHCII for activated microglia as indicated above the panels (scale bars 1 mm). Histological staining with FluoroJadeB for degenerating neurons and activated glia (see text for details) (scale bar 0.1 mm). Note that expression of human Tau is highest at 1.5 week p.i. and subsides later, paralleling the loss of NeuN immunoreactivity. The FJB signals in CA1 mark degenerating pyramidal neurons at 3 weeks p.i. but changes to an astroglial pattern at later time-points (see text for details). Note that at 3 weeks p.i. the loss of neurons and FJB positive signals in CA concurs with intense microgliosis, which subsides completely at 12 weeks p.i. while astrogliosis is much less specific in time and spatial distribution (see text for details).
Mentions: In sharp contrast, the intracerebral injection of AAV-Tau.P301L presented at first a very surprising outcome at 12 weeks p.i., because expression of human tau was detected in cortex but was hardly detectable in the hippocampus, i.e. where the virus was injected (Figure 2 A–C). Counterstaining for nuclei and in depth analysis resolved the apparent contradiction: expression of human protein Tau was low in pyramidal neurons in the hippocampus because of the nearly complete loss of pyramidal neurons in CA1/2 (Figure 2 A–C; compare injected to contra-lateral hemisphere). The dramatic nearly complete elimination of pyramidal CA neurons was confirmed by Nissl staining (data not shown) and by IHC for NeuN as marker for neuronal nuclei (Figure 3A, lower panels).

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