Accumulation of Filamentous Tau in the Cerebral Cortex of Human Tau R406W Transgenic Mice

Abstract

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).

Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)

“…In contrast to a recent model expressing the R406W tau mutation (Ikeda et al, 2005) (ϳ20% penetrance), we observed a highly consistent phenotype in bigenic mice that occurred with 100% penetrance. We believe the rapid onset of tau pathology (ϳ2.5 months) and the aggressive progression of cognitive decline and neurodegeneration avail an efficient and economical experimental model.…”

Divergent Pathways Mediate Spine Alterations and Cell Death Induced by Amyloid-β, Wild-Type Tau, and R406W Tau

“…Disease-relevant tau mutants differentially induce cell death in combination with A␤ It has been shown that overexpression of FTDP-17 tau mutants such as P301L and R406W in transgenic mice leads to the development of NFTs and neuronal degeneration (Lewis et al, 2000;Zhang et al, 2004). The accumulated tau was phosphorylated at disease-relevant residues (Ikeda et al, 2005). Combination with APP or A␤ increased tangle formation in P301L mice (Lewis et al, 2000;Götz et al, 2001).…”

Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

“…5,6 In frontotemporal lobar degeneration with tau gene mutation, their functional effects might be attributable to a loss of function mechanism by virtue of decreased microtubule binding but might also be attributable to a gain of toxic function because some of these mutations either increase binding to microtubules or increase the aggregation properties of the mutant tau proteins. Transgenic mice overexpressing wild-type human tau [7][8][9][10][11][12] or pathogenic mutant tau G272V, 13 P301L, 14 -16 P301S, 17,18 V337M, 19 and R406W 20,21 have been developed. Neurofibrillary tangles (NFTs) developed in mice expressing mutant tau, but the exact relationship between their formation and neuronal dysfunction and death has not been firmly established.…”