Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Abstract

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr¹⁸¹, Ser¹⁹⁹, Thr²³¹ and Thr²³⁵), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser³⁹⁶ and Ser⁴⁰⁴ in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure

“…The parental single Tau mutant tg mice that we use have been reported to display moderate alterations in tau accumulation [27], additionally, previous studies have shown that adding GSK3β enhances the pathology [28], therefore Tau/GSK3β bigenic mice were generated by crossing Tau tg mice expressing human Tau under the mThy-1 promoter with GSK3β tg mice in order to enhance tau phosphorylation. These double tg mice were subsequently used to evaluate the effects of CBL.…”

“…The mThy1-Tau (V337M and R406W) tg model has been shown to accumulate soluble p-Tau in the limbic system and to display spatial learning impairments [27]. The FTDP-17 R406W tau mutation has been described in an American, a Dutch, and a Japanese family [30–32].…”

“…However, it is unclear whether CBL might ameliorate the neurodegenerative pathology in models of FTLD. For this purpose we generated a new cross of the mutant Tau tg mice expressing human 4 repeat Tau (4R-Tau), bearing the missense mutations V337M and R406W, under the mThy-1 promoter [27] with GSK3β tg mice. The Tau/GSK3β double tg model displays biochemical and neuropathological features reminiscent of tauopathies including elevated levels of Tau phosphorylation and neurodegeneration.…”

Do age and sex impact on the absolute cell numbers of human brain regions?

“…a Total cell number; b number of neurons; c number of non-neuronal cells; d Mass. The lines in d represent significant negative correlations of cerebellar mass with age for men (blue), and women (red) memory deficits of aging, now attributed to the subcellular, molecular action of b-amyloid oligomers on dendrites (Cochran et al 2014) and synapses (Ferreira and Klein 2011), and of hyperphosphorilation of tau-protein on neuronal physiology (Flunkert et al 2013). Further reduction leads to the involvement of genes and epigenetic control (Sebolella et al 2012;Piaceri et al 2015).…”

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

“…Thus, excessive Tau phosphorylation alone may be necessary and sufficient for pathological impairment of neural function. Although some studies in Tau mutant mice indeed correlate the onset of behavioural deficits [19,20] as well as disruptions in critical cellular signalling pathways [21] with soluble phospho-Tau levels in the absence of an elevation of insoluble Tau levels, such a demonstration without the confounding influences of FTD mutations and/or gross Tau overexpression remains elusive. Equally, the demonstration of improved memory upon the suppression of FTD Tau expression, despite continued formation/persistence of NFTs [22,23] further supports the notion that soluble Tau phosphorylation is strongly connected with neuronal dysfunction.…”