Abstract
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-TauP301L 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.
Highlights
Abnormal deposition of the tau protein is the hallmark feature of tauopathies, which encompasses a growing list of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy, corticobasal degeneration (CBD) and chronic traumatic encephalopathy (CTE)
To assess the ability to model tauopathy with somatic brain transgenesis with associated virus serotype 1 (AAV1)-TauP301L on postnatal day 0, mice were harvested at 6 months of age and the level and distribution of human tau expression evaluated histologically (Fig. 1)
We measured human tau levels by a quantitative immunoassay, which demonstrated that the average level of human tau in AAV1TauP301L mice was 2.37 ± 0.087 ng/μg of brain tissue, which is significantly lower than rTg4510 mice that express ∼3.735 ± 0.057 ng/μg of human tau in the brain (Supplementary Material, Fig. S1b)
Summary
Abnormal deposition of the tau protein is the hallmark feature of tauopathies, which encompasses a growing list of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy, corticobasal degeneration (CBD) and chronic traumatic encephalopathy (CTE). The inflexible nature of the transgene prohibits the introduction of new tau mutations without the generation of an entirely new transgenic line To address these limitations, we have developed a novel mouse model in which adeno-associated virus serotype 1 (AAV1) was used to express the FTD-associated P301L human tau protein (AAV1-TauP301L) or control virus expressing GFP (AAV1-GFP) in C57BL/6 mice. While pathological changes were not associated with overt neuronal loss, the aberrant deposition of cleaved PSD95, a major postsynaptic scaffolding protein, is suggestive of significant structural changes within the synapse that may contribute to the behavioral abnormalities in exploration, anxiety, as well as learning and memory These results indicate that the AAV1-TauP301L model recapitulates biochemical and histological hallmarks, as well as neuroinflammation and behavioral deficits characteristic of tauopathy but that these effects occur independently of neuronal cell death
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