High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration

Jeanna M Wheeler,Linda Robinson,Halvor Juul,Elaine Loomis,Brian C Kraemer,Pamela J Mcmillan,Gerard D Schellenberg,John Q Trojanowski,Murray Raskind,Doori Jeong,Virginia M.Y Lee,Beth A Dombroski,Michiyo Iba,James B Leverenz,Marc A Dichter,George J Xu,Michele Hawk

doi:10.1186/s40478-015-0210-6

Abstract

IntroductionAccumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer’s disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease.ResultsWe generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence.ConclusionsFeatures of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0210-6) contains supplementary material, which is available to authorized users.

Highlights

Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer’s disease (AD) and other tauopathies
Previous studies demonstrated that pathological tau, not amyloid deposition, correlates with the cognitive decline seen in AD [1], and neurofibrillary degeneration coincides with neuronal loss in AD [2]
The model may have utility for studies of tau transmission as reported by Clavaguera et al [9] as well as for pre-clinical studies where the ability to assess target engagement at early time points preceding neurofibrillary degeneration is desirable, avoiding the time and cost involved in characterizing aged mice

Summary

Introduction

Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer’s disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. In AD, WT human tau forms the pathological tau species contributing to neuronal dysfunction and neurodegeneration. Previous work suggested that accumulation of pre-tangle conformations of tau drive progression in AD [3, 4]. To model sporadic tauopathy we overexpressed the most abundant isoform of WT human tau (1N4R) to provoke pathological changes associated with tauopathy. We generated a new mouse model with abundant overexpression of a normal human tau cDNA sequence that exhibits abundant pre-tangle tau neuropathology accompanied by behavioral abnormalities. The model may have utility for studies of tau transmission as reported by Clavaguera et al [9] as well as for pre-clinical studies where the ability to assess target engagement at early time points preceding neurofibrillary degeneration is desirable, avoiding the time and cost involved in characterizing aged mice

Methods

Results

Discussion

Conclusion