Genetic Background Influences the Propagation of Tau Pathology in Transgenic Rodent Models of Tauopathy

Abstract

Alzheimer's disease (AD), the most common tauopathy, is an age-dependent, progressive neurodegenerative disease. Epidemiological studies implicate the role of genetic background in the onset and progression of AD. Despite mutations in familial AD, several risk factors have been implicated in sporadic AD, of which the onset is unknown. In AD, there is a sequential and hierarchical spread of tau pathology to other brain areas. Studies have strived to understand the factors that influence this characteristic spread. Using transgenic rat models with different genetic backgrounds, we reported that the genetic background may influence the manifestation of neurofibrillary pathology. In this study we investigated whether genetic background has an influence in the spread of tau pathology, using hippocampal inoculations of insoluble tau from AD brains in rodent models of tauopathy with either a spontaneously hypertensive (SHR72) or Wistar-Kyoto (WKY72) genetic background. We observed that insoluble tau from human AD induced AT8-positive neurofibrillary structures in the hippocampus of both lines. However, there was no significant difference in the amount of neurofibrillary structures, but the extent of spread was prominent in the W72 line. On the other hand, we observed significantly higher levels of AT8-positive structures in the parietal and frontal cortical areas in W72 when compared to SHR72. Interestingly, we also observed that the microglia in these brain areas in W72 were predominantly phagocytic in morphology (62.4% in parietal and 47.3% in frontal), while in SHR72 the microglia were either reactive or ramified (67.2% in parietal and 84.7% in frontal). The microglia in the hippocampus and occipital cortex in both lines were reactive or ramified structures. Factors such as gender or age are not responsible for the differences observed in these animals. Put together, our results, for the first time, show that the immune response modulating genetic variability is one of the factors that influences the propagation of tau neurofibrillary pathology.

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer’s Disease

“…A large number of pieces of evidence support a prion-like model for tau spreading, consisting of abnormal proteins with the capacity to convert normal proteins into a pathological form. The inoculation of brain extracts from mice or humans with tauopathy into the brain of wild-type animals induced tau pathology in recipient animals and its propagation from the site of injection along neuronal connections (Clavaguera et al, 2009 , 2013 ; Lasagna-Reeves et al, 2012 ; Ahmed et al, 2014 ; Guo et al, 2016 ; Gibbons et al, 2017 ; Narasimhan et al, 2017 ; Smolek et al, 2019a , b ). Similar results were obtained when synthetic tau fibrils were injected into young mice overexpressing mutant human tau (P301S) which resulted as well in the formation of NFT-like inclusions that propagated from the injected sites to connected brain regions in a time-dependent manner (Iba et al, 2013 ).…”

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

“…Nevertheless, the increasing use of patient-derived brain lysates and the recent emergence of humanized tauopathy mouse models may be decisive in the search for a treatment capable of slowing disease progression or reversing its detrimental effects. Additionally, patient-derived tau seeding in rat models could also be further explored, as their larger brain size may make them better research models for characterizing tau PET tracers compared to mice [ 178 , 179 ]. Of note, robust cognitive deficits have thus far not been reported in seeding models.…”

Resveratrol targeting tau proteins, amyloid‐beta aggregations, and their adverse effects: An updated review

“…It has been shown that these abnormalities and aggregation of tau proteins are along with impairment in autophagy process (Ando et al, 2020). A newly published article has demonstrated that genetic background is a candidate involved in spread of tauopathy (Smolek et al, 2019). The aggregations of tau proteins are found in temporal, ventral, lateral, and primary cortical areas of brain.…”