. Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice. Nat Aging 9 January 2023 Nature Aging

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  1. This exciting study identifies a new and critical player of tau-mediated neurodegeneration, i.e., the production of retrotransposon-derived dsRNA that, in turn, plays a causal role in neuroinflammation. Their results demonstrate that tau-mediated dsRNA production is broadly conserved among humans, mice, and even flies, and that its inhibition can suppress neuroinflammation. This indicates that tau-mediated dsRNA production plays a fundamental role in neurodegeneration, providing an important therapeutic strategy against tauopathies.

    View all comments by Samuel Beck
  2. This very exciting work from the Frost lab builds on their previous work on the role of tau in driving neurodegeneration through chromatin remodeling. Now, they report that dsRNA is elevated in astrocytes of postmortem brain tissue from patients with progressive supranuclear palsy and Alzheimer's disease, in the brains of tau transgenic mice, and in the Drosophila model of tauopathy. In Drosophila, they identified specific tau-induced retrotransposons that form dsRNA, and they found that pathogenic tau and heterochromatin de-condensation causally drive dsRNA-mediated neuroinflammation. Overall, the study suggests that pathogenic tau-induced heterochromatin de-condensation and retrotransposon activation cause an elevation of inflammatory, transposable element-derived dsRNA in the adult brain, which may contribute to the neuronal degeneration seen in tauopathies.

    This is clearly an exciting study that continues to imply a role for tau beyond the microtubules in tauopathies. The use of both human brain tissue samples and animal models (Drosophila and mice) enhances the generality of the findings. However, it is important to understand that while the study provides strong evidence for links between tau-induced heterochromatin de-condensation, retrotransposon activation, and neuroinflammation, further research will be needed to understand whether these changes apply in other tauopathy models and to fully understand the underlying molecular mechanisms. For example, we don’t currently know whether these changes are due to a direct impact of tau on the chromatin and if yes, which form of tau. Phosphotau? Tau oligomers?

    Foundational work from Lester Binder’s group and more recent work from others in the field, especially Luc Buée and Marie-Christine Galas groups, has identified that tau localizes and binds to the DNA especially when non-phosphorylated. Accordingly, our ongoing work has further identified that this non-phosphorylated tau is important for nucleolar function. So, the question that has yet to be answered is whether pathogenic tau impacts the normal nuclear or DNA-binding function of non-phosphorylated tau that results in the changes observed, or if pathogenic tau directly binds the chromatin to cause these changes. These are questions that I hope future research will address.

    Moreover, previous studies on the nuclear role of tau have mostly focused on neuronal cells, although tau has been found in many cell types including those found outside the nervous system. This work suggests that nuclear tau may play a functional and pathogenic role in those other cell types, such as astrocytes. This nicely ties in with recent studies in the field that suggest non-neuronal mechanisms driving neurodegeneration in tauopathies.

    In conclusion, the study provides important new insights into the mechanisms of tau toxicity in tauopathies and provides strong justification for studying other functions of tau that are critical for us to better understand and treat tauopathies.

    View all comments by Mahmoud Bukar Maina
  3. This is a really interesting paper! I think there is a fair bit of evidence from numerous groups that transposable elements increase in neurodegenerative diseases. Josh Dubnau at Cold Spring Harbor Labs showed this in a fly ALS model. Josh Shulman at Baylor showed this informatically in humans. Frost’s article is nicely done and shows elevation of dsRNA in human brain and probes mechanisms using the fly. Three things are particularly striking to me:

    1. The increase in dsRNA occurs in mild cases, with Braak II/III. That is quite mild for the striking molecular pathology.
    2. Bess’ group sees dsRNA in PSP, so we know the culprit is tau, not Ab.
    3. In humans and mice, the increased dsRNA occurs in astrocytes. This is surprising because tau generally accumulates in neurons. Hence, it would seem hard to argue that tau directly causes the accumulation; instead the results suggests that the astrocytes must respond to tau accumulation in the neurons early on. Such intimate interactions between neurons and astrocytes are known. We have a nice paper in Nature Communications in which we report a really nice induction of pathology in human iPSC-derived assembloids (Ricnker et al., 2022). This article has a lot of information in it, but the point relevant to Frost’s paper is that we seed neurons in a two-dimensional culture stage, then a day later combine them with astrocytes to make three-dimensional assembloids. Although the astrocytes never see the tau, scRNAseq shows that nevertheless they immediately and dramatically respond to the neuronal pathology (Fig. 4 and 5 of our paper). All of this is to say that it is very clear that astrocytes respond quickly and deeply to neuronal pathology.

    I am not convinced that tau is directly causing the transposon activation in astrocytes, because the tau accumulates mostly in the neurons, with little (depending on the type of tauopathy) accumulating in astrocytes. Nevertheless, the demonstration of massive changes in transposon reactivity adds to the literature, and the finding that it occurs in astrocytes raises many important mechanistic questions that demand exploration. The transposons might also ultimately prove to be a very useful biomarker, although this was not addressed.

    References:

    . Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun. 2022 Oct 21;13(1):6275. PubMed.

    View all comments by Benjamin Wolozin
  4. This is an interesting paper. Just to note, the work in AD and PSP tissue, as well as the tau mice, is observational—they see evidence of change in dsRNA and its machinery at different stages of disease, but no further work is pursued. So many things are messed up in AD brains and the brains of mice with advanced pathology that it’s sometimes hard to get excited about such observations.

    Still, the findings suggest a mechanistic link between retrotransposon activity that produces dsRNA, and "pathogenic" tau that drives neurodegeneration and inflammation. All of this can be modulated by the helicase MDA5. The results are very interesting and exciting, but additional testing in mouse models with, perhaps, siRNA or knockout of aspects of the dsRNA system, or of MDA5, is needed to really appreciate the therapeutic potential of the work. Working with flies is useful, but limited in many regards, including their survival time. Notably, flies don't have astrocytes, which are important cells of interest here. Repeating/testing their hypothesis in mouse models, longitudinally, and including behavioral testing as well as anatomical and biochemical analyses, would really strengthen the therapeutic potential of targeting the dsRNA system or retrotransposons. 

    So, is this a plausible way that tau exerts neurotox? Maybe. The data presented are very convincing in the fly model. However, there may be many ways that tau executes its toxic effects in the brain. Also, whether this extends to other species, such as mouse models of human disease, is unknown due to the "acute" nature of disease development in flies and their limited lifespan, as mentioned above. The mechanistic underpinnings of disease in mammals may also be different. In addition, in the case of AD, there is Aβ accumulation early that may be involved in tau progression. That is not considered here, because the models are tau only. 

    In terms of additional observational work, it would be interesting to see how dsRNA, MDA5, and other intermediates change over time in Aβ mouse models, given that some phospho-tau or other "pathogenic" tau species develop to limited degrees in flies, which only express 4R tau (as does the mouse model the authors used). In AD, 3R tau species are also involved in disease and cause toxic effects. I wonder if pathogenic 3R tau species can also induce the effects seen here in the 4R models.

    View all comments by RR Robert Rissman

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