Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model.
Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-Tau(P301L) mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets.
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Casey
C
Cook
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Silvia S
SS
Kang
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Yari
Y
Carlomagno
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Wen-Lang
WL
Lin
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Mei
M
Yue
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Aishe
A
Kurti
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Mitsuru
M
Shinohara
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Karen
K
Jansen-West
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Emilie
E
Perkerson
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Monica
M
Castanedes-Casey
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Linda
L
Rousseau
Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Virginia
V
Phillips
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Guojun
G
Bu
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Dennis W
DW
Dickson
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA fryer.john@mayo.edu Petrucelli.leonard@mayo.edu.
Leonard
L
Petrucelli
Neurobiology of Disease Graduate Program, Mayo Graduate School, Jacksonville, FL 4500 San Pablo Road, Jacksonville, FL 32224, USA fryer.john@mayo.edu Petrucelli.leonard@mayo.edu.
John D
JD
Fryer
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000648:ultrastructure*; D016923:Cell Death; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging; D009474:Neurons / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins