Abstract
Although it has been suggested that the co-expression of multiple pathological proteins associated with neurodegeneration may act synergistically to induce more widespread neuropathology, experimental evidence of this is sparse. We have previously shown that the expression of Thr175Asp-tau (tauT175D) using somatic gene transfer with a stereotaxically-injected recombinant adeno-associated virus (rAAV9) vector induces tau pathology in rat hippocampus. In this study, we have examined whether the co-expression of human tauT175D with mutant human TDP-43 (TDP-43M337V) will act synergistically. Transgenic female Sprague-Dawley rats that inducibly express mutant human TDP-43M337V using the choline acetyltransferase (ChAT) tetracycline response element (TRE) driver with activity modulating tetracycline-controlled transactivator (tTA) were utilized in these studies. Adult rats were injected with GFP-tagged tau protein constructs in a rAAV9 vector through bilateral stereotaxic injection into the hippocampus. Injected tau constructs were: wild-type GFP-tagged 2N4R human tau (tauWT; n = 8), GFP-tagged tauT175D 2N4R human tau (tauT175D, pseudophosphorylated, toxic variant, n = 8), and GFP (control, n = 8). Six months post-injection, mutant TDP-43M337V expression was induced for 30 days. Behaviour testing identified motor deficits within 3 weeks after TDP-43 expression irrespective of tau expression, though social behaviour and sensorimotor gating remained unchanged. Increased tau pathology was observed in the hippocampus of both tauWT and tauT175D expressing rats and tauT175D pathology was increased in the presence of cholinergic neuronal expression of human TDP-43M337V. These data indicate that co-expression of pathological TDP-43 and tau protein exacerbate the pathology associated with either individual protein.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterized by progressive death of upper and lower motor neurons with death on average 3–5 years after diagnosis [8]
In the choline acetyltransferase (ChAT)-tTA/tetracycline response element (TRE)-TDP-43M337V rats human TAR-DNA binding protein of 43 kDa (TDP-43) expression was observed at 30 days post DOX reduction in both ventral horn motor neurons (Fig. 1d) and cortical neurons (Fig. 2d) consistent with previous studies [14]
The hippocampal expression of human TDP-43 on DOX withdrawal was variable in the ChAT-tTA /TRE-TDP43M337V rats, varying from extremely weak to strong expression
Summary
Amyotrophic lateral sclerosis (ALS) is characterized by progressive death of upper and lower motor neurons with death on average 3–5 years after diagnosis [8]. Moszczynski et al Acta Neuropathologica Communications (2019) 7:170 of true disease processes as they do not account for the presence of comorbid pathologies. These models constitutively expressed toxic proteins throughout the central nervous system and may have been expressing individual toxic constructs to such a high degree that any subtle effects of the combined expression may have been missed. TDP-43 is present in motor neuron pathology in most cases of ALS [17], and tau protein pathology has been demonstrated in hippocampal and anterior cingulate brain tissues in the vast majority of cases of ALS with cognitive impairment (ALSci) [32, 37]. Beyond ALSci, the coexistence of TDP-43 and tau pathology has been described in the form of concomitant argyrophilic grain disease in ALS [30], Alzheimer’s disease and dementia with Lewy bodies [12]
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