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Title: | AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice | Authors: | Jaworski, Tomasz DEWACHTER, Ilse Lechat, Benoit Croes, Sophie Termont, Annelies Demedts, David Borghgraef, Peter Devijver, Herman Filipkowski, Robert K Kaczmarek, Leszek Kügler, Sebastian Van Leuven, Fred |
Issue Date: | 2009 | Publisher: | PUBLIC LIBRARY SCIENCE | Source: | PloS one, 4 (10) (Art N° ARTN e7280) | 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. 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. |
Notes: | associated data : https://figshare.com/articles/AAV_Tau_Mediates_Pyramidal_Neurodegeneration_by_Cell_Cycle_Re_Entry_without_Neurofibrillary_Tangle_Formation_in_Wild_Type_Mice/146350 | Keywords: | Neuroscience;neurodegeneration;mediates;neurofibrillary;mice;re-entry;wild-type;pyramidal;tangle;aav-tau;cell-cycle | Document URI: | http://hdl.handle.net/1942/30297 | ISSN: | 1932-6203 | e-ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0007280 | ISI #: | 000270354200007 | Rights: | 2009 Jaworski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Figure_S4.tif | Published version | 4.96 MB | TIFF | View/Open |
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Table_S1.pdf | Published version | 80.37 kB | Adobe PDF | View/Open |
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