. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.


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  1. The title of this remarkable paper in Nature Cell Biology highlights two key findings: that a tau pathology can be transmitted in vivo, and that it spreads through the brain. The former is a feature of transmissible prions (a characteristic as enigmatic as to elude comprehension), while the latter addresses a key feature of the human Alzheimer pathology, one that despite major recent achievements has not been fully modeled in transgenic mice.

    The study uses two mouse strains: ALZ17 mice express high levels of wild-type human tau but reveal only a modest pathology: amyotrophy in the absence of obvious neuronal cell loss and, despite massive hyperphosphorylation of tau, no formation of tau-containing neurofibrillary lesions. In contrast, P301S mice express, at levels comparable to the ALZ17 mice, a mutant form of tau found in familial cases of frontotemporal dementia. Although rarer than the P301L mutation, this mutation causes an earlier onset of pathology in humans. This may explain why the P301S mice present with a particularly robust phenotype, characterized by neurodegeneration in the spinal cord and an abundance of neurofibrillary tangles.

    In their study, the research teams lead by Markus Tolnay and Michel Goedert investigated whether aggregation of tau can be transmitted in mice. They intracerebrally injected diluted brain extracts from six-month-old P301 mice into three-month-old ALZ17 mouse and analyzed the injected brains for up to 15 months post-injection. They found that in ALZ17 mice, the P301S extract induced the formation of neurofibrillary tangles as revealed by Gallyas silver impregnation, and reactivity with antibody AT100 that is specific for tau phosphorylated pathologically at the phospho-epitope Thr212/Ser 214.

    Interestingly, Clavaguera and colleagues found that Gallyas reactivity (i.e., tangle formation) was not confined to the site of injection, but rather induced up to 2 mm distant of the injection site. A carefully performed time-course analysis suggests a stereotypical mode of spreading (a feature characteristic of Alzheimer disease). It would be interesting to determine how pronounced the pathology of P301S mice would be and how the pathology would spread when injected with a P301S extract, and whether an injection of the P301S extract into the cerebellum (a site spared from pathology) would be sufficient to induce a pathology in this brain area.

    Another remarkable finding is that insoluble rather than soluble tau is responsible for the induction of a tau pathology. Here, a follow-up study could determine how long the injected material needs to be around in the brain to exert toxicity and how long it does persist in the mouse brain, questions that could be addressed with biotinylated or fluorescently labeled material.

    The paper is a rich source of findings that are worthwhile to be taken up experimentally: Induction of a tau pathology seems to be mediated by oligodendroglia (a cell type not affected by tau pathology in the parental P301S mice). Then, there is evidence for a role of secreted or diffuse tau in propagating tauopathy, rather than of merely cytoplasmic tau. Does this species need to be truncated, specifically phosphorylated or be of a particular higher order assembly? Finally, it seems that there are different species of tau (as in prion diseases) with some species inducing spreading of pathology and others neurodegeneration. As the P301S mice show massive motor neuron loss in spinal cord, it might be worthwhile injecting the P301S extract into brain stem or spinal cord of ALZ17 mice to determine whether in this cellular environment, the tau species present in the P301S extract would induce both, spreading of a ”Gallyas pathology” and degeneration of motor neurons.

    In conclusion, this is a true milestone paper that has brought the field forward quite a bit, causing a paradigm shift in tau research. While we are left with many answers there are also a lot of challenging, new questions to be addressed.

  2. Clavaguera and colleagues demonstrate in this elegant study that an injection of a brain extract from P301S tau mice induces aggregation of wild-type tau in mice expressing human or mouse tau. The pathology spreads to anatomically connected brain regions in mice transgenic for human tau but not in wild-type mice expressing only mouse tau. As discussed, tau expression levels may influence the spread, and human tau may also be more prone to aggregate than mouse tau.

    These interesting and important in vivo findings tie nicely in with recent cell culture data (1), and support the view that clearance of extracellular tau may have a therapeutic utility, ideally in concert with removal of pathological intracellular tau (2,3). As previously reported, extracellular tau may not only be derived from dead cells but may be secreted and have an extracellular function (4). As discussed in more detail elsewhere (3), it is then conceivable that clearance of extracellular tau can enhance secretion of intracellular tau through a shift in equilibrium, and indirectly reduce pathological tau burden within cells. Furthermore, not only may glia take up extracellular tau but also neurons. This uptake/secretion pathway may be particularly prominent under pathological conditions, and could explain the anatomical spread of tangles during disease progression. All amyloid diseases may be transmissible under certain conditions (5).


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  3. This is a provocative and exceptionally well-done study that convincingly demonstrates the CNS spread of tau pathology induced by the injection of P301S transgenic (tg) mouse brain homogenates containing P301S pathological mutant tau into the brains of wild-type tau tg and non-tg mice. However, I do think the use of the term “transmission” in the paper is unfortunate because this conjures up the idea that tauopathies may be infectious diseases like transmissible spongiform encephalitises (TSEs), as exemplified by mad cow disease and Creutzfeldt-Jacob disease (CJD). The concern comes from the fact that Alzheimer’s disease (AD) is the most common neurodegenerative tauopathy and this report could raise unwarranted worries on the part of the public or public health officials that AD is infectious and could be spread by contact with the millions of AD patients throughout the world. Although many studies by Carlton Gajdusek (e.g., see Godec et al., 1991) and others over the years failed to show reproducible evidence of transmission of AD by injecting AD brain homogenates along the lines in the Clavaguera et al. study, a report just over 20 years ago suggesting that this occurred (see Manuelidis et al., 1988) did precipitate undue public concern that AD might be transmissible/infectious. That said, the studies here show in a convincing manner that, following brain injection of P301S mutant tau pathological material, there is some form of cell-to-cell spread of pathological tau in the form of paired helical filaments (PHFs), which are amyloids just like prion, Aβ, and α-synuclein fibrils in CJD, AD, and Parkinson disease (PD), respectively. These PHFs are the building blocks of neurofibrillary tangles (NFTs), hallmark brain lesions of AD, as well as other tauopathies known as frontotemporal lobar degeneration (FTLD) of the tau type, or FTLD-tau, as exemplified by Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and others (see MacKenzie et al., 2008). Thus, the findings here are important for understanding mechanisms underlying the onset as well as the progression of AD and related tauopathies.

    I do not think the major implications of this paper are that there should be public health concerns that AD might be an infectious disease like CJD for the reasons discussed above. However, the paper has significant potential implications for how we think of disease pathogenesis for AD, other tauopathies, and other neurodegenerative brain amyloidoses like PiD, PSP, CBD, and PD. For example, can the model systems here explain the stereotypical manner in which the tau, Aβ, and α-synuclein amyloid pathologies appear to evolve (“spread”) over time with disease progression in most cases of these disorders? Obviously, more must be done to take this research further to explain these phenomena, but even the phenomena themselves can be used to argue against the cell-to-cell spread of each of these pathologies or combinations of them as exemplified by studies showing that the evolution and distribution of tau pathology in AD, PiD, CBD, and PSP are very different with different regions and brain cells being affected in different tauopathies. Indeed, NFTs occur commonly in both neurons and glia in some of these disorders, but mainly in neurons in other tauopathies despite the fact that the affected neurons are surrounded by glial cells which are unaffected by tau pathology. Endothelial cells in blood vessels that permeate brain profusely also do not show tau pathology in tauopathies. However, studies like the one here may provide strategies to explain these phenomena as well as the selective vulnerability of one group of neurons and glia to develop tau or other amyloid pathology compared to other groups of cells that appear resistant to accumulating tau pathology within the brain of a patient with AD, PSP, PiD, or CBD. These model systems also could address the issue of how/why patients with diseases like AD show other amyloid deposits, since α-synuclein amyloid deposits as Lewy bodies commonly occur in AD brains in addition to plaques and tangles, or why plaques and tangles occur in close proximity in some but not all affected brain regions in AD. To address this issue experimentally, we conducted studies similar to those in the current report, and we showed that injections of human AD PHFs into rat brains induces aggregation and deposition of Aβ (see Shin et al., 1993) and that tau and α-synuclein can induce each other to form amyloid fibrils in vivo and in vitro (see also Lee et al., 2004 and Giasson et al., 2003), yet the mechanisms of how this occurs and the significance of this are poorly understood. Further, AD patients also show evidence of accumulations of TDP-43 deposits, but TDP-43 pathology is neither congophilic nor shows features of amyloid, but it is characteristic of FTLD of the TDP-43 type or FTLD-TDP and ALS, and a recent study of AD patients demonstrated correlations between the presence of TDP-43 and α-synuclein pathologies and cognitive deficits in AD patients in addition to those attributable to plaques and tangles (see Nelson et al., 2008), so these additional TDP-43 and α-synuclein pathologies appear to be clinically relevant for AD.

    These studies should be followed to address the types of issues mentioned above, and many others, and it would have been interesting if the authors had done studies to see if their P301S tg mouse brain injections induced Aβ and α-synuclein deposits, but that may be in the works already.


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