Tau isoform regulation is region‐ and cell‐specific in mouse brain

Abstract

Tau is a microtubule-associated protein implicated in neurodegenerative tauopathies. Alternative splicing of the tau gene (MAPT) generates six tau isoforms, distinguishable by the exclusion or inclusion of a repeat region of exon 10, that are referred to as 3-repeat (3R) and 4-repeat (4R) tau, respectively. We developed transgenic mouse models that express the entire human MAPT gene in the presence and absence of the mouse Mapt gene and compared the expression and regulation of mouse and human tau isoforms during development and in the young adult. We found differences between mouse and human tau in the regulation of exon 10 inclusion. Despite these differences, the isoform splicing pattern seen in normal human brain is replicated in our mouse models. In addition, we found that all tau, both in the neonate and young adult, is phosphorylated. We also examined the normal anatomic distribution of mouse and human tau isoforms in mouse brain. We observed developmental and species-specific variations in the expression of 3R and 4R-tau within the frontal cortex and hippocampus. In addition, there were differences in the cellular distribution of the isoforms. Mice transgenic for the human MAPT gene exhibited higher levels of neuronal cell body expression of tau compared to wild-type mice. This neuronal cell body expression of tau was limited to the 3R isoform, whereas expression of 4R tau was more "synaptic like", with granular staining of neuropil rather than in neuronal cell bodies. These developmental and speciesspecific differences in the regulation and distribution of tau isoforms may be important to the understanding of normal and pathologic tau isoform expression.

Role of tau protein on neocortical and hippocampal oscillatory patterns

“…Also, an increased tau expression in frontotemporal lobes was observed (Fig. 1C) as previously reported (Goerdert et al, 1989;Trojanowski et al, 1989;Santa-Maria et al, 2005;McMillan et al, 2008). Gene expression was also analyzed (see Methods) and the only transcript that showed a drastic decrease in tau 2/2 compared to tau 1/1 mice was the tau RNA (tau 2/2 vs. tau 1/1 : fold change 25,42; P < 10…”

“…This result is supported not only by the hippocampal location of the main generators of extracellular theta oscillations (Buzsaki, 2002) but also by the elevated expression of tau in hippocampus (Goerdert et al, 1989;Trojanowski et al, 1989;Santa-Maria et al, 2005;McMillan et al, 2008). Early stages of development have been demonstrated to be critical for the formation of synaptic connections and functional circuits in many regions of the nervous system, including the hippocampus and neocortex (Wagner and Luhmann, 2006;Sun and Luhmann, 2007;Blankenship and Feller, 2010).…”

“…Tau function has been studied in vitro or in cultured cells where it plays an important role in facilitating microtubules stabilization as well as axonal establishment and elongation during neuronal morphogenesis (Drubin and Kirschner, 1986;Caceres and Kosik, 1990). On the other hand, tau is unevenly distributed in the mammalian brain exhibiting its highest expression over frontotemporal neocortex and hippocampus (Goedert et al, 1989;Trojanowski et al, 1989;Santa-Maria et al, 2005;McMillan et al, 2008). In vivo-tau function has also been explored in tau-deficient (tau 2/2 ) mice, although scarce differences were found when compared with their wild-type (wt) counterparts (Perez et al, 2009).…”

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

“…Comparison between 6-and 12-month old PLB2 Tau samples suggested a relative reduction in the abundance of hTau in the soluble fraction of forebrain lysates with age (Fig 2.B, p=0.07, respectively). Overall Tau protein expression (pooled pan Tau AT-5 immunoreactive bands, corresponding to ~50 kDa: 0N4R, ~55 kDa: 1N4R and ~60 kDa: 2N4R adult Tau isoforms, McMillan et al, 2008), was not altered relative to agematched controls at 6 or 12-months of age ( Fig. 2.A+C, p>0.05), likely due to the unaltered levels of the major 50 kDa species.…”

The Microtubule-Dissociating Tau in Neurological Disorders

“…Furthermore, recent studies in transgenic mouse models that express the entire human MAPT gene in the presence and absence of the mouse Mapt gene show differences between mouse and human tau in the regulation of exon 10 inclusion during development and in the young adult. In addition, it was observed species-specific variations in the expression of 3R-and 4R-tau within the frontal cortex and hippocampus during the development as well as in cell distribution of the isoforms (McMillan P et al, 2008).…”