Local replication of tau seeds—not their spread from region to region in the brain—drives tau accumulation in Alzheimer’s disease. That is the provocative conclusion of a chemical kinetics study published October 29 in Science Advances. Researchers led by Tuomas Knowles and David Klenerman, both of the University of Cambridge, U.K., and Bradley Hyman of Massachusetts General Hospital, Boston, applied kinetic modeling of tau aggregation and spread to multiple sources of experimental data, ranging from the measurement of tau seeds extracted from human brain samples to tau PET imaging in living people.
- Kinetic model finds that local replication of tau seeds sets the pace of tau accumulation in AD.
- Spreading plays a negligible role.
- Past Braak III, tau aggregates double every five years in neocortex.
- In mice overexpressing tau, aggregates double every two weeks.
The scientists found that by Braak Stage III and beyond, spreading between regions accounts for a negligible amount of tau accumulation. Instead, local replication of tau aggregates within each region appears to be the rate-limiting factor. Furthermore, they report that, on average, it takes five years for an aggregate of tau in the neocortex to double. Notably, the findings suggest that by Braak Stage III, aggregation-ready tau must already be widely distributed throughout the neocortex, rather than just beginning its prion-like tear from the entorhinal cortex.
“The study fits with the idea that each neuron, or local set of neurons, has the ability to cause more replication of tau,” said Dennis Selkoe of Brigham and Women’s Hospital in Boston. “This analysis calls into question the emphasis in our field on the concept of neuron-to-neuron passage,” he added. Selkoe and others have expressed skepticism about the prominence of proteopathic propagation in neurodegenerative disease research (Apr 2016 Alzforum webinar).
“This is an interesting and thoughtful modeling approach to understanding the temporal and spatial characteristics of tauopathy in the Alzheimeric brain,” commented Lary Walker of Emory University in Atlanta. “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,” he added.
Still, Selkoe and other commentators noted limitations to the new model. For one, they ask whether it is valid to use different measurements of tau accumulation—such as tau seeding capacity versus neuropathology versus tau PET tracer uptake—within the same kinetic model.
Knowles told Alzforum that the study was motivated by a simple question: What is the primary driver of tau’s aggregation throughout the brain in AD? To answer it, first author Georg Meisl and colleagues first derived a mathematical model of tau accumulation. It accounts for the rate of tau aggregation as well as spreading throughout the brain. Importantly, the model was agnostic to mechanisms of spread, and was limited to the analysis of spread between brain regions, rather than between cells within a given region.
Equipped with a mathematical equation that took both replication and spreading into account, the researchers set out to answer their first question: Is the accumulation of tau aggregates in the neocortex limited by the rate of tau spreading, or replication? To answer it, they plugged different kinds of experimental data into their model. They used data from three studies that had quantified tau seeding activity in different brain regions in people who had died in different stages of AD (DeVos et al., 2018; Furman et al., 2017; Kaufman et al., 2018). Other postmortem studies quantified tau accumulation via immunohistochemistry (Gómez-Isla et al., 1997; Qian et al., 2017). Finally, the researchers included data from tau PET studies, which infer tangle accumulation via tracer uptake (Sanchez et al., 2021).
Data from all these studies suggested that the distribution of tau aggregates fundamentally changes at Braak Stage III, when aggregates start being detected outside of the medial temporal lobe and in the neocortex. Because clinical symptoms also begin at this stage, the researchers designated Braak stage III as “T=0” in their equation, and modeled tau kinetics from this stage onward.
They found that the experimental data fit tightly with the kinetic model only when the system is replication-limited. In other words, tau's progression throughout the brain can be explained mostly by the replication rate of tau seeds within each region, not by the rate tau seeds spread between regions.
What Curbs Tau? Using experimental data, scientists modeled which process dictates the accumulation of tau pathology in human brain. In one scenario, spread limits the accumulation of tau (left). In another, replication dictates the pace of accumulation (right). [Courtesy of Meisl et al., Science Advances, 2021.]
Next, the scientists asked their model to calculate the doubling time of tau aggregates in different brain regions from Braak Stage III onward. Things were slow. On average, tau seeds doubled once every five years. This varied depending on which experimental dataset was used, ranging from three to nine years. However, regardless of how tau was measured—by seeding assay, immunocytochemistry, or PET—the model consistently found that tau aggregates replicate on the order of several years.
“While the proposed models include a number of assumptions, the consistency of the results across different datasets is compelling,” commented Gil Rabinovici of the University of California, San Francisco (full comment below).
If it takes so long for one tau seed to become two tau seeds, then how does the neocortex manage to fill with tangles as AD advances? The only explanation for this, the researchers claim, is that by Braak Stage III, tau seeds are already widely distributed throughout the neocortex, where they continue to form and replicate locally as disease worsens. How those aggregates get there in the first place—whether by spreading that took place prior to Braak Stage III, and/or by de novo aggregation in each region—this study could not address.
Meisl also put the model to use in P301S-tau transgenic mice, which overexpress aggregation-prone human tau throughout the brain. Lo and behold, the tau seed doubling time was only two weeks—lightning-fast compared to that observed in the human brain.
This implies that the human brain may be better equipped than the mouse brain to ward off tau aggregation. In support of this idea, the authors found that P301S tau replicates nearly as fast in the mouse brain as it does in a test tube, whereas in the human brain, wild-type tau replicates two orders of magnitude more slowly than it does in vitro.
The findings demonstrate how both in vitro and mouse models come up short as models of tauopathy, Selkoe said.
“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,” commented Walker. Klenerman made a similar point, noting that improving upon the brain’s inherent anti-aggregation activity by just a little bit could have a strong impact on slowing tauopathy progression.
The trouble is, most of the tau-targeted therapies in development take aim at tau spreading, Knowles noted. “Our analysis shows that there are fundamental reasons why spreading is not a good target,” he said. “By Braak Stage III, spreading is effectively irrelevant from an intervention point of view.”
Rabinovici agreed that, if correct, the findings could have major implications for drug development.
Selkoe believes therapeutics that take aim at intracellular tau, such as anti-tau “intrabodies” or antisense oligonucleotides that douse tau expression, might be best suited to target this process. Knowles and Klenerman added that therapies aimed at beefing up the neuronal anti-aggregation machinery, such as supporting chaperones or enhancing protein degradation, could also do the trick.
To the mind of Tharick Pascoal, University of Pittsburg, Pennsylvania, the results call for further study of what exactly catalyzes local tau seeding in Braak III. This could be amyloid—and other mechanisms, too (full comment below).—Jessica Shugart
- DeVos SL, Corjuc BT, Oakley DH, Nobuhara CK, Bannon RN, Chase A, Commins C, Gonzalez JA, Dooley PM, Frosch MP, Hyman BT. Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain. Front Neurosci. 2018;12:267. Epub 2018 Apr 24 PubMed.
- Furman JL, Vaquer-Alicea J, White CL 3rd, Cairns NJ, Nelson PT, Diamond MI. Widespread tau seeding activity at early Braak stages. Acta Neuropathol. 2017 Jan;133(1):91-100. Epub 2016 Nov 22 PubMed.
- Kaufman SK, Del Tredici K, Thomas TL, Braak H, Diamond MI. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART. Acta Neuropathol. 2018 Jul;136(1):57-67. Epub 2018 May 11 PubMed.
- Gómez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997 Jan;41(1):17-24. PubMed.
- Qian J, Hyman BT, Betensky RA. Neurofibrillary Tangle Stage and the Rate of Progression of Alzheimer Symptoms: Modeling Using an Autopsy Cohort and Application to Clinical Trial Design. JAMA Neurol. 2017 May 1;74(5):540-548. PubMed.
- Sanchez JS, Becker JA, Jacobs HI, Hanseeuw BJ, Jiang S, Schultz AP, Properzi MJ, Katz SR, Beiser A, Satizabal CL, O'Donnell A, DeCarli C, Killiany R, El Fakhri G, Normandin MD, Gómez-Isla T, Quiroz YT, Rentz DM, Sperling RA, Seshadri S, Augustinack J, Price JC, Johnson KA. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography. Sci Transl Med. 2021 Jan 20;13(577) PubMed.
No Available Further Reading
- 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.