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Experimental Genetics Group
PLoS One. 2009 Oct 1;4(10):e7280. Jaworski T1, Dewachter I1, Lechat B1, Croes S1*, Termont A1*, Demedts D1, Borghgraef P1, Devijver H1, Filipkowski RK2, Kaczmarek L1, Kügler S3, Van Leuven F1**. 1Experimental Genetics Group, Department of Human Genetics, KULeuven, Leuven, Belgium. 2Lab of Molecular Neurobiology, Nencki Institute, Warsawa, Poland. 3Center of Molecular Physiology of the Brain (CMPB), Department of Neurology, University Medicine Göttingen, Göttingen, Germany. *Current address: reMYND nv, Leuven, Belgium. **Corresponding author. 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.  FULL TEXT |
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