Overexpression of Wild-Type Murine Tau Results in Progressive Tauopathy and Neurodegeneration

Abstract

Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies. Abnormal accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles (NFTs), is the defining pathological feature of neurodegenerative diseases termed tauopathies. Six major tau protein isoforms are generated in adult human brain by alternative splicing of the tau (MAPT) gene, 1,2 and studies of mutations within this gene have provided insight into potential mechanisms for the pathological aggregation of tau proteins.3,4 With use of a single isoform of mutant human tau, transgenic mice have been generated (reviewed in 5 ) that recapitulate many features of human tauopathy; however, most tauopathies are not associated with specific MAPT mutations. Because normal and mutant tau proteins appear to have functional differences, 6 -8 the mechanism of tau pathology development, neuronal loss, and interactions with other proteins may also differ between sporadic tauopathies and cases linked to specific mutations. Previous attempts to create a wild-type tauopathy model through overexpression of a single wild-type human tau isoform have generally led to minimal pathological changes. Although these models have been useful in studying early aspects of tauopathy, they do not mimic normal gene regulation or tau isoform profiles in the brain. Development of a mouse model overexpressing the entire human tau transgene (8c mice) was expected to overcome this limitation. However, these mice failed to elicit notable tau pathology, but did result in a significant shift in exon 10...

Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: a light and electron microscopy study

“…The most frequently encountered pathology is the splitting of the lamellae of myelin sheaths, resulting in myelin disruption and, sometimes, swelling of the nerve fibers. Myelin disruption is also common in many other TG mouse models of tauopathy (Adams et al 2009; Desai et al 2009; Higuchi et al 2002; Leroy et al 2007; Lewis et al 2000; Lin et al 2003b; Lin et al 2005). Somewhat less common but much more striking are the large, highly irregular, swollen myelinated nerve fibers that generate profiles in which it is difficult to identify the axon.…”

Modelling early responses to neurodegenerative mutations in mice

“…However, unlike transgenic mice overexpressing human P301L mutant tau [26][27][28][29][30], neither heterozygous nor homozygous P301L-tau-knockin mice showed any signs of neurofibrillary pathology or any detrimental behavioural changes at any age. Critically, pretangle changes, such as tau hyperphosphorylation and/or tau aggregation, are also absent, despite the fact that they are often a feature of transgenic lines that overexpress wildtype human or mouse tau that are generally regarded as less pathogenic [24,[31][32][33][34][35]. In fact, a wild-type tau transgenic line show intense staining with an antibody that recognizes both human and murine tau (N-Tau5) indicating that the transgene is expressed at high levels in just a small percentage of these neurons in this model.…”

Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer’s Disease

“…40) Furthermore, murine wild-type tau transgenic mice show a progressive increase in hyperphosphorylated tau pathology with age. 41) Increased tau expression likely accelerates AD pathology in people with DS. The treatment with calcineurin-NFAT signaling activators caused a decrease in tau gene expression (Fig.…”