Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain

Abstract

Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies. Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.

Astrogliopathy in Tauopathies

“…Seeding of human tau from homogenates of AD and tauopathies with neuronal and glial components is also observed after inoculation into the brain of wild-type mice [178,179].…”

“…Seeding and spreading of abnormal tau occurs after inoculation of brain homogenates from AD and other tauopathies into the brain of transgenic mice over-expressing human tau or mutated tau [163,[173][174][175]. The type of deposits in the inoculated animals seems to be disease-dependent in the few tauopathies so far studied, which suggests the occurrence of different species or strains of tau depending on the disease [176][177][178]. However, these models have a natural substrate of abnormal tau production that makes it difficult to separate the propagation itself from what is induced.…”

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

“…Wild type animals injected with tau extracts from human P301S mice resulted in Gallyas silver and AT100 positive threads and coiled bodies at the site of injection [71], but no NFTs or progression of disease were observed at 6 and 12 months post-injection. In a later study, injection of up to 8 µg of tau protein induced tau pathology, as well as spreading in non-transgenic mice [74]. Furthermore, neuropil threads and oligodendroglial coiled bodies were observed in wild type mice following injection of AD, TD or PSP brain extracts; only astroglial tau inclusions positive for AT8 or AT100 were observed post injection of CBD brain extracts [70].…”

“…Moreover, in most of these cases tau pathology in the form of NFTs, NTs and argyrophilic grains were observed. On the contrary, few studies only demonstrated presence of hyper phosphorylated tau inclusions after seeding of tau from human AD without formation of NFTs [27,72,74,106]. In these studies, spreading of tau pathology from site of injection was observed.…”

“…In contrast to tau from rodent and human brain extracts, various forms of synthetic tau oligomers or filaments did not induce NFTs or NTs; however, in all the cases the presence of hyper phosphorylated tau was reported [74,103,104,[108][109][110]. Only one study showed NFT like tau pathology and presence of conformationally modified tau protein in the tau inclusions [103].…”