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

Autor:	Koller EJ; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Gonzalez De La Cruz E; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Machula T; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Ibanez KR; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Lin WL; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA., Williams T; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Riffe CJ; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Ryu D; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Strang KH; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Liu X; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Janus C; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA., Golde TE; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Dickson D; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA., Giasson BI; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Chakrabarty P; Department of Neuroscience, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Oct 01; Vol. 28 (19), pp. 3255-3269.
DOI:	10.1093/hmg/ddz151
Abstrakt:	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. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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