Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy

Abstract

Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain axis in CNS homeostasis, and therefore we set out to examine the isoform profile and phosphorylation state of tau in the enteric nervous system (ENS) under physiological conditions and in tauopathies. Surgical specimens of human colon from controls, Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) patients were analyzed by Western Blot and immunohistochemistry using a panel of anti-tau antibodies. We found that adult human ENS primarily expresses two tau isoforms, localized in the cell bodies and neuronal processes. We did not observe any difference in the enteric tau isoform profile and phosphorylation state between PSP, PD and control subjects. The htau mouse model of tauopathy also expressed two main isoforms of human tau in the ENS, and there were no apparent differences in ENS tau localization or phosphorylation between wild-type and htau mice. Tau in both human and mouse ENS was found to be phosphorylated but poorly susceptible to dephosphorylation with lambda phosphatase. To investigate ENS tau phosphorylation further, primary cultures from rat enteric neurons, which express four isoforms of tau, were pharmacologically manipulated to show that ENS tau phosphorylation state can be regulated, at least in vitro. Our study is the first to characterize tau in the rodent and human ENS. As a whole, our findings provide a basis to unravel the functions of tau in the ENS and to further investigate the possibility of pathological changes in enteric neuropathies and tauopathies.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0568-3) contains supplementary material, which is available to authorized users.

Tau accumulates in Crohn's disease gut

“…There were no correlations between the expression levels of tau, age and disease duration ( Figure S2). We have recently shown that 1N3R and 0N4R are the two main tau isoforms expressed in the adult human ENS and that these two isoforms are phosphorylated under physiological conditions (16). Using 3R and 4R isoform specific antibodies, we found that both 1N3R and 0N4R tau isoforms were upregulated in the inflamed area in CD ( Figure 1B).…”

“…It should be noted however that the pathological distinction among these disorders is sometimes not so clear as the co-occurrence of alpha-synuclein and tau deposits has been reported in PD (12). Several independent studies have shown that enteric neurons, like their CNS counterparts, also express alpha-synuclein (13)(14)(15) and tau (16,17) and we recently demonstrated that alpha-synuclein is upregulated in inflamed segments of Crohn's colon (18). These latter findings, together with the results of recent epidemiological (19,20) and genetical studies (21), support the existence of a close relationship between Parkinson's and Crohn's disease.…”

Tau accumulates in Crohn’s disease gut

“…We have recently shown that the isoform profile of tau differed between the ENS and the CNS, with 1N3R and 0N4R being the two main tau isoforms expressed in adult human enteric neurons (16). In addition, we did not observe any changes in tau expression, phosphorylation or truncation of colonic samples from patients suffering from the prototypical tauopathy progressive supranuclear palsy (PSP).…”

“…We first analyzed the expression levels of tau in colonic biopsies of CD and controls by Western are the two main tau isoforms expressed in the adult human ENS and that these two isoforms are phosphorylated under physiological conditions (16). Using 3R and 4R isoform specific antibodies, we found that both 1N3R and 0N4R tau isoforms were upregulated in the inflamed area in CD ( Figure 1b).…”

“…It should be noted however that the pathological distinction among these disorders is sometimes not so clear as the co-occurrence of alpha-synuclein and tau deposits has been reported in PD (12). Several independent studies have shown that enteric neurons, like their CNS counterparts, also express alpha-synuclein (13)(14)(15) and tau (16,17) and we recently demonstrated that alphasynuclein is upregulated in inflamed segments of Crohn's colon (18). These latter findings, together with the results of recent epidemiological and genetical studies (reviewed in (19)), support the existence of a close relationship between Parkinson's and Crohn's disease.…”