Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy

Emily J. Koller, Elsa Gonzalez De La Cruz, Timothy Machula, Kristen R. Ibanez, Wen Lang Lin, Tosha Williams, Cara J. Riffe, Daniel Ryu, Kevin H. Strang, Xuefei Liu, Christopher Janus, Todd E. Golde, Dennis Dickson, Benoit I. Giasson, Paramita Chakrabarty

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3255-3269
Number of pages15
JournalHuman molecular genetics
Volume28
Issue number19
DOIs
StatePublished - Oct 1 2019

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Tauopathies
Alzheimer Disease
Frontotemporal Dementia
Pick Disease of the Brain
Pathology
Immunogenetics
Gene Transfer Techniques
Dependovirus
Memory Disorders
Morbidity
Mutation
Neuropathology

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Koller, E. J., Gonzalez De La Cruz, E., Machula, T., Ibanez, K. R., Lin, W. L., Williams, T., ... Chakrabarty, P. (2019). Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. Human molecular genetics, 28(19), 3255-3269. https://doi.org/10.1093/hmg/ddz151

Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. / Koller, Emily J.; Gonzalez De La Cruz, Elsa; Machula, Timothy; Ibanez, Kristen R.; Lin, Wen Lang; Williams, Tosha; Riffe, Cara J.; Ryu, Daniel; Strang, Kevin H.; Liu, Xuefei; Janus, Christopher; Golde, Todd E.; Dickson, Dennis; Giasson, Benoit I.; Chakrabarty, Paramita.

In: Human molecular genetics, Vol. 28, No. 19, 01.10.2019, p. 3255-3269.

Research output: Contribution to journalArticle

Koller, EJ, Gonzalez De La Cruz, E, Machula, T, Ibanez, KR, Lin, WL, Williams, T, Riffe, CJ, Ryu, D, Strang, KH, Liu, X, Janus, C, Golde, TE, Dickson, D, Giasson, BI & Chakrabarty, P 2019, 'Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy', Human molecular genetics, vol. 28, no. 19, pp. 3255-3269. https://doi.org/10.1093/hmg/ddz151
Koller EJ, Gonzalez De La Cruz E, Machula T, Ibanez KR, Lin WL, Williams T et al. Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. Human molecular genetics. 2019 Oct 1;28(19):3255-3269. https://doi.org/10.1093/hmg/ddz151
Koller, Emily J. ; Gonzalez De La Cruz, Elsa ; Machula, Timothy ; Ibanez, Kristen R. ; Lin, Wen Lang ; Williams, Tosha ; Riffe, Cara J. ; Ryu, Daniel ; Strang, Kevin H. ; Liu, Xuefei ; Janus, Christopher ; Golde, Todd E. ; Dickson, Dennis ; Giasson, Benoit I. ; Chakrabarty, Paramita. / Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. In: Human molecular genetics. 2019 ; Vol. 28, No. 19. pp. 3255-3269.
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AU - Janus, Christopher

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