Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy
Open accessAbstract
Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer’s disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants—WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick’s disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.
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In the pre-deposit cohort, ptau levels were considerably lower in AAV-S320F tau expressing mice.
“The levels of ptau were considerably lower in the AAV-S320F tau expressing mice (Fig. 2F–H), as expected from our previous data in nonTG mice (10).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [10]
In the pre-deposit cohort, normalizing MC1 inclusion numbers to ptau burden confirmed that only S320F tau showed self-aggregation properties.
“Normalizing the MC1 inclusion numbers to the ptau burden confirmed that only S320F tau showed self-aggregation properties in the pre-deposit cohort (Fig. S3C), also consistent with our previous data in nonTG mice (10).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [10]
Human WT tau and P301L tau do not form NFT tau following 6 months of sustained expression in mice.
“Human WT tau and P301L tau does not form NFT tau following 6 months of sustained expression in mice, whereas the S320F tau showed self-aggregating properties in cell culture (11) and in nonTG mice (10).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [10]
S320F tau shows self-aggregating properties in nonTG mice.
“whereas the S320F tau showed self-aggregating properties in cell culture (11) and in nonTG mice (10).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [10]
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Tauopathies: new perspectives and challenges
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Self-citation
- Authors
- Koller, E. J., Gonzalez De La Cruz, E., Machula, T., Ibanez, K. R., Lin, W.-L., Williams, T., Riffe, C. J., Ryu, D., Strang, K. H., Liu, X., Janus, C., Golde, T. E., Dickson, D., Giasson, B. I., & Chakrabarty, P.
- Affiliations
- University of Florida (US)
- Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA
- Mayo Clinic in Florida (US)
- Corresponding author
- Chakrabarty, Paramita
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-06-07
- Volume
- 28
- Issue
- 19
- Pages
- 3255-3269
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2955896363
- Cited by
- 63
- References
- 8
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 13 · 2022: 17 · 2021: 5 · 2020: 4
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG055798)
- Barbara’s Dream Fund for Frontotemporal Dementia Research and Education
- National Institute on Aging (T32 AG061892)
- Florida Department of Health (7AZ25)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tauopathy, P301L tau mutation, tau hyperphosphorylation, tau tangles, Alzheimer's disease, frontotemporal dementia, Pick's disease, adeno-associated virus, memory impairment, neuroinflammation, cognitive impairment, synaptic changes, mouse model
- MeSH terms
- Animals, Behavior, Animal, Central Nervous System, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Mutation, Phosphorylation, tau Proteins, Pick Disease of the Brain, Tauopathies, Mice, Frontotemporal Dementia
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