The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model

Abstract

Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice.

Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons

“…However, it remains unclear whether such impairments represent an early causative effect or a late consequence in disease (Götz et al, 2006;Bodea et al, 2016). Particularly, the transport of APP and its subcellular mislocalization have putative implication in Alzheimer's disease, with tau playing a crucial role in controlling APP trafficking (Stamer et al, 2002;Goldsbury et al, 2007).…”

Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

“…A single tau gene mutation induces NFT formation and neuronal loss with 100% penetration. Moreover, overexpression of human FTDP-17 tau induces NFT formation, neuronal loss, and behavioral deficits in mice (5)(6)(7)(8)(9)(10)(11)(12).…”

Traumatic Brain Injury Exacerbates Neurodegenerative Pathology: Improvement with an Apolipoprotein E-Based Therapeutic

“…As previously described (Dawson et al, 2007), equal amounts of protein samples (50 mg) were electrophoresed on a denaturing 4-20% SDS-PAGE gel and transferred onto nitrocellulose membranes. The membranes were then blocked in 5% milk and incubated in AT8 antiphosphorylated tau antibody (1:150) overnight at 48C.…”

“…Stereological analysis was performed on microglia that were positive for F4/80 immunostaining (the whole hippocampus, median n ¼ 5), neurons that were positive for NeuN staining (hippocampal pyramidal layer of CA1-CA3, median n ¼ 3), and intracellular accumulations that were 4G8-immunopositive (hippocampal pyramidal layer of CA1-CA3, median n ¼ 5). Stereological analysis was performed using the optical fractionator method on a Nikon 218912 light microscope interfaced with the StereoInvestigator software package (MicroBrightField, Williston, VT) as described previously (Dawson et al, 2007(Dawson et al, , 2010. The optical fractionator is an unbiased counting method, which is independent of the size, shape, and orientation of the cells to be counted.…”