A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau

Abstract

Human tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by distinct clinical features, typical histopathological structures, and defined ratio(s) of three-repeat and four-repeat tau isoforms within pathological aggregates. How the optional microtubule-binding repeat of tau influences this differentiation of pathologies is understudied. We have previously generated and characterized transgenic rodent models expressing human truncated tau aa151-391 with either three (SHR24) or four microtubule-binding repeats (SHR72). Here, we compare the behavioral and neuropathological hallmarks of these two transgenic lines using a battery of tests for sensorimotor, cognitive, and neurological functions over the age range of 3.5-15 months. Progression of sensorimotor and neurological deficits was similar in both transgenic lines; however, the lifespan of transgenic line SHR72 expressing truncated four-repeat tau was markedly shorter than SHR24. Moreover, the expression of three or four-repeat tau induced distinct neurofibrillary pathology in these lines. Transgenic lines displayed different distribution of tau pathology and different type of neurofibrillary tangles. Our results suggest that three- and four-repeat isoforms of tau may display different modes of action in the diseased brain.

Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice

“…Tau truncations at the C-terminal, HT368 [39], HT391 [25][26][27][28]40], or HT421 [41][42][43], and the beginning of the proline-rich domain HT151 [25,27,28,40,41] lead to a dramatic increase in the toxicity and aggregation potential of tau when expressed in rodents. Transgenic rodent models utilizing the same truncation as the AAV used in this study recapitulate the entire biochemical cascade of tau pathology [25,27,28,40,44]. The expression of truncated tau in these models, however, is driven by Thy1 promotor, and strong neurofibrillary pathology is located mainly in the brainstem which is associated with paralysis, i.e., sensorimotor impairment rather than cognitive impairment.…”

Neuropathological changes and cognitive deficits in rats transgenic for human mutant tau recapitulate human tauopathy

“…Notably, the first report of transgenic rat lines expressing human truncated tau demonstrated the brain occurrence of sarkosyl extracted tau fibrillary material consisting of both endogenous and human tau (Filipcik et al, 2012; Zilka et al, 2006). Furthermore, these truncated models described the presence of inclusions within the spinal cord and brainstem, resulting in motor and coordination deficits early and independently of neuronal loss (Valachova et al, 2018). In these models, no neuron loss was detected in the hippocampus or cortex (Filipcik et al, 2012; Koson et al, 2008).…”