Impaired burrowing is the most prominent behavioral deficit of aging htau mice

Philippine Camilla Geiszler,Matthew Richard Barron,Marie-Christine Pardon

doi:10.1016/j.neuroscience.2016.05.004

Philippine Camilla Geiszler, Matthew Richard Barron + Show 1 more

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https://doi.org/10.1016/j.neuroscience.2016.05.004

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Journal: Neuroscience	Publication Date: May 7, 2016
Citations: 24	License type: cc-by

Affiliation: University of Nottingham

Abstract

htau mice are deficient of murine tau but express all six human tau isoforms, leading to gradual tau misprocessing and aggregation in brain areas relevant to Alzheimer’s disease. While histopathological changes in htau mice have been researched in the past, we focused here on functional consequences of human tau accumulation.htau mice and their background controls – murine tau knock-out (mtau−/−) and C57Bl/6J mice – underwent a comprehensive trial battery to investigate species-specific behavior, locomotor activity, emotional responses, exploratory traits, spatial and recognition memory as well as acquisition, retention and extinction of contextual fear at two, four, six, nine and twelve months of age.In htau mice, tau pathology was already present at two months of age, whereas deficits in food burrowing and spatial working memory were first noted at four months of age. At later stages the presence of human tau on a mtau−/− background appeared to guard cognitive performance; as mtau−/− but not htau mice differed from C57Bl/6J mice in the food burrowing, spontaneous alternation and object discrimination tasks. Aging mtau−/− mice also exhibited increased body mass and locomotor activity.These data highlight that reduced food-burrowing performance was the most robust aspect of the htau phenotype with aging. htau and mtau−/− deficits in food burrowing pointed at the necessity of intact tau systems for daily life activities. While some htau and mtau−/− deficits overlap, age differences between the two genotypes may reflect distinct functional effects and compared to C57Bl/6J mice, the htau phenotype appeared stronger than the mtau−/− phenotype at young ages but milder with aging.

Highlights

Tau is a microtubule-associated protein (MAP) which regulates microtubule dynamics and transport of mitochondria in neuronal axons (Medina and Avila, 2014)
Semiquantitative analysis of the western blots showed that htau mice expressed more total (Fig. 1E) and phosphorylated (Fig. 1F and G) tau than C57Bl/6J mice irrespective of their age (F(1,27) = 62.53, p < 0.0001 for Tau-46, F(1,27) = 42.08, p < 0.0001 for CP13 and F(1,30) = 46.52, p < 0.0001 for PHF1), but the CP13/Tau-46 and PHF1/Tau-46 ratios did not differ between htau and C57Bl/6J mice (F (1,27) = 0, p = 0.9943 for CP13/Tau-46 and F(1,29) = 0.1, p = 0.7578 for PHF-1/Tau-46; data not shown); as was the case for the case for PHF1/Tau-46 ratio (F (1,29) = 0.001, p = 0.9566, data not shown)
No significant age or age Â genotype interaction effects were found for either Tau-46 and CP13 levels or the CP13/Tau-46 and PHF1/ Tau-46 ratios, data not shown). This is in apparent contrast with illustrative examples of immunoblots from htau brains which suggest that CP13 increases with age while total tau and PHF1 remains stable, this was not supported by semiquantitative analyses (Andorfer et al, 2003)

Summary

Introduction

Tau is a microtubule-associated protein (MAP) which regulates microtubule dynamics and transport of mitochondria in neuronal axons (Medina and Avila, 2014). Altered human tau (htau) mice are void of murine tau but express all six, non-mutated, human tau isoforms instead (Andorfer et al, 2003) This is of specific relevance to AD which is not associated with mutated forms of tau (Andorfer et al, 2003). In accordance with the histopathological progression of AD, htau mice display an age-related increase of hyperphosphorylated tau in cortical and hippocampal areas; somatic redistribution of tau, indicated by the presence of insoluble tau in dendrites, as early as at two months of age and accumulation of phosphorylated tau in the cell body at three months of age; tau aggregates are observed by nine months of age, resembling later stage NFTs in humans (Andorfer et al, 2003). Htau mice display an increasing inflammatory phenotype from three months of age onward (Bhaskar et al, 2010; Garwood et al, 2010) as well as decreasing cortical thickness from ten-months-of-age onward, and neuronal cell loss at seventeen months of age (Andorfer et al, 2005)

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