AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice.
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.
Experimental Genetics Group, Department of Human Genetics, KULeuven-Campus, Leuven, Belgium.
Tomasz
T
Jaworski
Ilse
I
Dewachter
Benoit
B
Lechat
Sophie
S
Croes
Annelies
A
Termont
David
D
Demedts
Peter
P
Borghgraef
Herman
H
Devijver
Robert K
RK
Filipkowski
Leszek
L
Kaczmarek
Sebastian
S
Kügler
Fred
F
Van Leuven
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D000229:Dependovirus / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000737:chemistry*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins