Variable tau accumulation in murine models with abnormal prion protein deposits

Abstract

The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases.

Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies

“…Similar patterns and distribution of p-tau were seen in brains of B6 mice inoculated with BSE agents of all three types: classical, H-type, and L-type 31 . The largest amounts of p-tau were observed in the brains of B6 mice inoculated with L-BSE agent.…”

“…No p-tau was detected in brain sections of uninoculated age-matched control B6 mice probed with anti-tau antibodies (AT8 or Thr231) or in BSE-infected B6 mice incubated without primary antibody. In short, p-tau accumulated widely in the brains of B6 mice infected with both typical and atypical BSE agents 31 (Table) in the same places as PrP TSE deposits.…”

“…In contrast, the brains of VM mice infected with 87V scrapie contained abundant amyloid plaques and both coarse and fine-punctate deposits of PrP TSE . Brains of terminally ill C57BL mice infected with ME7 scrapie contained small amounts of p-tau in most areas with spongiform degeneration 31 . The brains of terminally ill VM Wt mice infected with 87V scrapie contained deposits of p-tau within and adjacent to the margins of PrP TSE amyloid plaques; p-tau was also observed in the same regions where diffuse nonamyloid PrP TSE deposits occurred 31 (Table).…”

“…To explore further the association between p-tau and PrP while eliminating the potential confounding effects of aging, unrelated diseases, drug treatment, agonal changes and postmortem delay inevitable in human autopsy cases and to expand the study from nonhuman primates to small animals, we analyzed several murine models. All rodent tissues examined and described in this review were produced in previous transmission experiments 27,28,29,30,31 performed under licence from the UK Home Office in accordance with the Animals (Scientific Procedures) Act 1986. The severe tauopathy seen in squirrel monkeys infected with classical SQ-BSE 19 led us to study a line of transgenic mice from which the murine PRNP gene was deleted and then engineered to express a bovine PrP with a six-octapeptide repeat region ("bovinized knock-in" B6 mice) 28 ; we analyzed B6 mice intracerebrally inoculated with classical BSE agent from a bovine brain and also analyzed B6 mice inoculated with brain suspensions from cattle with two atypical forms of BSE: "heavy" or H-type BSE and bovine amyloidogenic spongiform encephalopathy (also called "light" or L-type BSE) 29 .…”

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

“…Although the process of prion conversion and PrP Sc formation depends mainly on the presence of PrP C , recent studies revealed that it can be affected by the concomitant presence of intracellular amyloids of other neurodegeneration-related proteins (20). In the case of tau protein, this assumes clinical relevance as some cases were documented where prion pathology co-exists with tau deposits (33)(34)(35). To assess the effect of tau fibrils on PrP Sc levels, we exposed a neuroblastoma cell line persistently infected with RML prion strain (ScN2a RML) to two different concentrations of tau K18 amyloids and we analysed the PK-resistant PrP Sc at different timepoints (Fig.…”