Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy

Abstract

The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt−/− background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.Tauopathies are a group of neurodegenerative diseases showing characteristic deposits of the microtubule-associated protein tau in the form of intracellular neurofibrillary tangles in the central nervous system. Alzheimer's disease (AD) is the most common tauopathy as well as the most prevalent neurodegenerative disorder worldwide. However, while AD patients' brains are characterised by tauopathic neuropathology, a genetic association of AD with the MAPT locus has not been unequivocally established [1][2][3][4][5] . In 1998, several groups showed that mutations in the MAPT gene are sufficient to cause a rare familial neurodegenerative disorder termed frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [6][7][8][9] . The MAPT locus is also strongly associated with the sporadic tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) which is likely explained by haplotype-specific regulation of alternatively-spliced exons [10][11][12][13] . More recently, a multitude of gene association and genome-wide association studies (GWAS) have identified MAPT as a highly significant genetic risk factor for sporadic Parkinson's disease (PD), despite the lack of obvious tau tangles in the majority of PD patients [14][15][16][17][18] . More recently, imbalances in tau isoform ratios and rod-like tau aggregates have been described in Huntington's disease 19 . In summary, the association of tau with several common neurodegenerative diseases either in the form of pathological inclusions, or as a genetic risk factor, demonstrates that t...

Chronic Sodium Selenate Treatment Restores Deficits in Cognition and Synaptic Plasticity in a Murine Model of Tauopathy

“…We found that vehicle-treated Tg mice displayed a marked increase in locomotor and exploratory activity during the initial habituation to the test environment and the dark phase of their activity cycle. This higher activity level, which was corrected by selenate treatment, is reminiscent of reports of hyperactivity in other Tau mouse models such as P301S (Przybyla et al, 2016 ), rTg4510 (Joly-Amado et al, 2016 ; Jul et al, 2016 ; Blackmore et al, 2017 ; Wang et al, 2018 ), MAPT-N296H (Wobst et al, 2017 ), N279K (Taniguchi et al, 2005 ) and a triple repeat mutant tau transgenic mouse line (Rockenstein et al, 2015 ). Of note, a Mapt −/− model on a B6129PF3/J genetic background also displayed hyperactive behavior (Biundo et al, 2018 ).…”

FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism

“…Surprisingly, most of the skipped exons occurred in genes that have pre-synaptic functions such as synaptic vesicle recycling, transport, and exocytosis, which could at least partially explain alterations in synaptic vesicle dynamics and neurotransmitter release in FXS model mice (Deng et al, 2013;Ferron et al, 2014;Broek et al, 2016). Furthermore, a number of skipped exons in Fmr1 KO have been linked to neurological disorders such as autism (skipped microexon 4 in Cpeb4; Irimia et al, 2014;Parras et al, 2018;Quesnel-Vallie `res et al, 2016), Alzheimer's disease (skipped exon 7 in APP; Fragkouli et al, 2017;Rockenstein et al, 1995), Parkinson's disease (skipped exon 3 in Mapt; Lai et al, 2017;Wobst et al, 2017), and intellectual disabilities (skipped exon 12 in Cnksr2; Houge et al, 2012).…”

Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders

“…Our laboratory uses high capacity bacterial and P1-phage artificial chromosome vectors (BACs and PACs) to express whole genomic loci in culture and applies homologous recombination technology to manipulate the large inserts with base-pair accuracy. We have previously used these vector systems to express the human MAPT locus in neuronal cell culture models and demonstrated MAPT locus expression is under developmental and cell-type specific regulation [ 26 ] and in transgenic mouse models express all six adult tau isoforms [ 27 ]. Here, we applied an analogous strategy to generate genomic DNA p MAPT -H1 and p MAPT -H2 expression vectors with identical upstream and downstream sequence, differing only at sites of haplotype variation.…”