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Meisl G, Hidari E, Allinson K, Rittman T, DeVos SL, Sanchez JS, Xu CK, Duff KE, Johnson KA, Rowe JB, Hyman BT, Knowles TP, Klenerman D. In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease. Sci Adv. 2021 Oct 29;7(44):eabh1448. PubMed.
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Emory University
This is an interesting and thoughtful modeling approach to understanding the temporal and spatial characteristics of tauopathy in the Alzheimeric brain. The findings indicate that both the replication and spreading of tau seeds contribute to the progression of tauopathy, but that the local replication of the seeds prevails after Braak Stage III. It seems that, as tauopathy passes through Stage III, long-distance spreading becomes increasingly secondary because tau seeds are already widely distributed in the brain. In addition, the burgeoning population of sick and dying neurons might release seeds locally to be taken up and replicated by other cells, while at the same time losing their ability to transport seeds to interconnected sites.
In Alzheimer's disease, it is not possible to fully disentangle Aβ and tau; the authors speculate that the transition that occurs around Braak Stage III might be related to the rapid development of Aβ plaques at this time. In this light, it could be informative to determine how toxic oligomeric forms of both tau and Aβ—which are not evident histologically or via in vivo imaging—fit into the scheme. Might a shift in the molecular diversity of tau assemblies play into the Stage III transition? The prion protein, for instance, has been reported to constitute both infectious (seeding-competent) and toxic varieties that have different temporal and pathobiologic properties (Sandberg et al., 2011).
One translational implication of the model is that inhibiting the formation of tau seeds, rather than blocking spread, is the more promising means of impeding tauopathy. In addition, the model indicates that the human brain may be relatively adept at slowing the growth and replication of tau seeds; understanding how it does so could disclose new therapeutic objectives for Alzheimer's and possibly other tauopathies as well.
References:
Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. 2011 Feb 24;470(7335):540-2. PubMed.
View all comments by Lary WalkerUCSF
This study represents an innovative, multidisciplinary effort to address a key question in the field: What are the most important mechanisms that drive the progression of tau pathology, a harbinger to neurodegeneration and cognitive decline in Alzheimer’s disease? By applying chemical modeling to an impressively diverse collection of datasets (ranging from seeding assays to quantitative neuropathology to tau PET), the investigators conclude that, at least at the symptomatic stage of AD (Braak Stage greater than III), local replication rather than distal spread drives increases in neocortical tau burden.
While the proposed models include a number of assumptions, the consistency of the results across different datasets is compelling.
If correct, the findings may have significant implications for drug development, guiding us to target the elements of tau biology that are most likely to impact disease progression. Even though clinical trials of tau-targeting therapies are well underway, this study highlights how little we actually know about the specific molecular mechanisms that drive tau aggregation and spread in AD.
One wonders also if the kinetics of tau spread will be similar in other tauopathies, such as PSP, CBD, CTE, Pick’s, etc., or if they will vary depending on the specific structure and biochemistry of tau aggregates and the connectivity and susceptibility of the brain regions afflicted in each disease.
Overall I found this to be a thought-provoking paper that raises many important questions for the field to address in future work.
View all comments by Gil RabinoviciUniversity of Pittsburgh
Meisl and colleagues showed results suggesting that tau seed accumulation distributes from Braak III to neocortex, preferentially via local replication rather than spreading. This is an interesting paper, in which the authors were able to organize complex mathematical concepts, experimental designs, and models into an elegant framework to describe tau seeds accumulation. Previous studies have proposed models to describe tau propagation, but I think Meisl's paper did a particularly good job of justifying mathematical assumptions with plausible biological inferences and some supporting experimental data.
The authors’ results invite further studies. Their results showing that tau seeds distribute faster after Braak III are in line with previous postmortem and in vivo studies suggesting Braak III as a milestone for the development of AD dementia. Interestingly, they also found tau seeds in low concentrations in neocortical regions, even before Braak III. These results together suggest that further studies could be designed to elucidate the mechanistic underpinnings associated with the catalysis of existing tau seeding in Braak III, including, but not limited to, the role of amyloid.
I would like to see more experiments supporting a comparison between replication and spreading of tau seeds, which, in my opinion, was heavily influenced by mathematical assumptions such as the chosen models.
In summary, this interesting study adds new elements and raises new questions to advance our understanding of tau propagation in AD.
View all comments by Tharick PascoalMake a Comment
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