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Increasing tau 4R tau levels exacerbates hippocampal tau hyperphosphorylation in the hTau model of tauopathy but also tau dephosphorylation following acute systemic inflammation

Barron, Matthew R; Gartlon, Jane; Dawson, Lee A; Atkinson, Peter J; Pardon, Marie-Christine

Authors

Matthew R Barron

Jane Gartlon

Lee A Dawson

Peter J Atkinson

Marie-Christine Pardon



Abstract

Inflammation is considered a mechanistic driver of Alzheimer's disease, thought to increase 15 tau phosphorylation, the first step to the formation of neurofibrillary tangles (NFTs). To further 16 understand how inflammation impacts the development of tau pathology, we used (hTau) mice which 17 express all 6, non-mutated, human tau isoforms, but with an altered ratio of tau isoforms favouring 3R 18 tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R. Such imbalance pattern 19 has been related to susceptibility to NFTs formation, but whether or not this also affects susceptibility 20 to systemic inflammation and related changes in tau phosphorylation is not known. To reduce the 21 predominance of 3R tau by increasing 4R tau availability, we bred hTau mice on a heterozygous mTau 22 background and compared the impact of systemic inflammation induced by lipopolysaccharide (LPS) 23 in hTau mice hetero-or homozygous mTau knockout. 24 Three-month-old male wild type (Wt), mTau +/-, mTau-/-, hTau/mTau +/-and hTau/mTau-/-mice 25 were administered 100, 250 or 330µg/kg of LPS or its vehicle PBS (i.v., n=8-9/group). Sickness 26 behaviour, reflected by behavioural suppression in the spontaneous alternation task, hippocampal tau 27 phosphorylation, measured by western immunoblotting, and circulating cytokine levels were 28 quantified 4h after LPS administration. The persistence of the LPS effects (250µg/kg) on these 29 measures, and food burrowing behaviour, was assessed at 24h post-inoculation in Wt, mTau +/-and 30 hTau/mTau +/-mice (n=9-10/group). 31

Journal Article Type Article
Journal Frontiers in Immunology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
APA6 Citation Barron, M. R., Gartlon, J., Dawson, L. A., Atkinson, P. J., & Pardon, M. (in press). Increasing tau 4R tau levels exacerbates hippocampal tau hyperphosphorylation in the hTau model of tauopathy but also tau dephosphorylation following acute systemic inflammation. Frontiers in Immunology, https://doi.org/10.3389/fimmu.2020.00293
DOI https://doi.org/10.3389/fimmu.2020.00293
Keywords Inflammation; Lipopolysaccharide; Alzheimer's disease; mouse model; tauopathies; 13 Tau isoforms imbalance 14
Publisher URL https://www.frontiersin.org/articles/10.3389/fimmu.2020.00293/abstract