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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

AAV-mediated expression of APP.SLA in wild-type mouse brain.Intracerebral injection of 10E8 transducing units (t.u.) AAV-APP.SLA vector in wild-type mice (n = 3) analyzed 12 weeks p.i. A, B: IHC for APP and its metabolites with Mab 6E10 on brain sections after antigen retrieval with formic acid [18]. Red square in panel B (middle) is enlarged in right panel. C: IHC for amyloid peptides with Mab 3D6; red square in middle panel is enlarged in right panel. D: histochemical staining with compound X-34 for protein aggregates [41] of AAV-APP.SLA injected mouse (left) and from an APP.V717I transgenic mouse (age 22 months) (right panel) as positive control for amyloid pathology as described [24], [29]. Scale bars panel A 1 mm, others as indicated.
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pone-0007280-g001: AAV-mediated expression of APP.SLA in wild-type mouse brain.Intracerebral injection of 10E8 transducing units (t.u.) AAV-APP.SLA vector in wild-type mice (n = 3) analyzed 12 weeks p.i. A, B: IHC for APP and its metabolites with Mab 6E10 on brain sections after antigen retrieval with formic acid [18]. Red square in panel B (middle) is enlarged in right panel. C: IHC for amyloid peptides with Mab 3D6; red square in middle panel is enlarged in right panel. D: histochemical staining with compound X-34 for protein aggregates [41] of AAV-APP.SLA injected mouse (left) and from an APP.V717I transgenic mouse (age 22 months) (right panel) as positive control for amyloid pathology as described [24], [29]. Scale bars panel A 1 mm, others as indicated.

Mentions: Initially, brains were analyzed 12 weeks after intracerebral injection of AAV-vectors in wild-type mice (age 3–6 months). Expression of APP.SLA was pronounced in pyramidal neurons in CA and cortex (Figure 1A). Antibody 6E10 [25] revealed intense intraneuronal accumulation of APP metabolites (Figure 1B), while antibody 3D6, specific for amyloid peptides [26] showed granular intracellular amyloid deposits (Figure 1C). Amyloid plaques were not detectable at 12 weeks p.i. of APP.SLA (Figure 1D).


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)

AAV-mediated expression of APP.SLA in wild-type mouse brain.Intracerebral injection of 10E8 transducing units (t.u.) AAV-APP.SLA vector in wild-type mice (n = 3) analyzed 12 weeks p.i. A, B: IHC for APP and its metabolites with Mab 6E10 on brain sections after antigen retrieval with formic acid [18]. Red square in panel B (middle) is enlarged in right panel. C: IHC for amyloid peptides with Mab 3D6; red square in middle panel is enlarged in right panel. D: histochemical staining with compound X-34 for protein aggregates [41] of AAV-APP.SLA injected mouse (left) and from an APP.V717I transgenic mouse (age 22 months) (right panel) as positive control for amyloid pathology as described [24], [29]. Scale bars panel A 1 mm, others as indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0007280-g001: AAV-mediated expression of APP.SLA in wild-type mouse brain.Intracerebral injection of 10E8 transducing units (t.u.) AAV-APP.SLA vector in wild-type mice (n = 3) analyzed 12 weeks p.i. A, B: IHC for APP and its metabolites with Mab 6E10 on brain sections after antigen retrieval with formic acid [18]. Red square in panel B (middle) is enlarged in right panel. C: IHC for amyloid peptides with Mab 3D6; red square in middle panel is enlarged in right panel. D: histochemical staining with compound X-34 for protein aggregates [41] of AAV-APP.SLA injected mouse (left) and from an APP.V717I transgenic mouse (age 22 months) (right panel) as positive control for amyloid pathology as described [24], [29]. Scale bars panel A 1 mm, others as indicated.
Mentions: Initially, brains were analyzed 12 weeks after intracerebral injection of AAV-vectors in wild-type mice (age 3–6 months). Expression of APP.SLA was pronounced in pyramidal neurons in CA and cortex (Figure 1A). Antibody 6E10 [25] revealed intense intraneuronal accumulation of APP metabolites (Figure 1B), while antibody 3D6, specific for amyloid peptides [26] showed granular intracellular amyloid deposits (Figure 1C). Amyloid plaques were not detectable at 12 weeks p.i. of APP.SLA (Figure 1D).

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