27 Mar 2025

Eight years ago, people were amazed by the first high-resolution glimpse into the core of tau fibrils extracted from the brain of a person who had had Alzheimer’s disease. Since those iconic back-to-back C-shaped structures came into view, scientists have uncovered numerous other tau contortions underlying various tauopathies. By 2021, there were enough published structures to draw a phylogenetic tree of sorts, linking distinct tau twists to different diseases (Oct 2021 news).

Four years later, it is time for an update. Michel Goedert and Sjors Scheres of the MRC Laboratory of Molecular Biology, Cambridge, England, U.K., who led most of the structural studies, expand on some branches and add an entirely new one to the tau family tree. These additions are based on structures that Scheres, Goedert, and other scientists have recently solved. For example, they discovered tau filaments striking the AD-tau pose in brain samples from people with FTD caused by V337M and R406W tau mutations, while carriers of P301L or P301T mutations harbored two entirely new folds. Moreover, three rare conditions—subacute sclerosing panencephalitis, amyotrophic lateral sclerosis/Parkinsonism-Dementia Complex, and vacuolar tauopathy—were found to share a fold with chronic traumatic encephalopathy. The classification scheme blurs lines between tau filament structures and diseases. Marc Diamond, University of Texas Southwestern Medical Center in Dallas, thinks the updated tree is helpful in considering what might be common origins of different tauopathies.

The most recent additions came on March 5, when, in Nature Structural and Molecular Biology, Scheres, Goedert, and colleagues reported the V337M-tau and R406W-tau core structures were a spot-on match with the one first found in AD back in 2017, and then later in familial British dementia (FBD), familial Danish dementia (FDD), and primary age-related tauopathy (PART) (Jul 2017 news; Shi et al., 2021). Using cryo-EM, first author Chao Qi and colleagues mapped paired helical filaments (PHFs) in three V337M-tau cases that were nearly identical to those in AD, as well as AD-like straight filaments (SFs) in one these cases. In another of them, they found an additional, and previously unknown, triple filament, featuring a core with three tau molecules, each folding into a J-like configuration resembling that taken by said straight filaments (image below). Separately, in two R406W carriers, the scientists resolved AD-like PHFs, but no straight or triple filaments.

C-ing Double. In the frontal cortex of a V337M-tau mutation carrier with FTD, the core structure of paired helical filaments (left) and straight filaments (middle) matched those of AD-tau, while a triple-filament configuration was new (right). [Courtesy of Qi et al., Nature Structural and Molecular Biology, 2025.]

The findings placed V337M/R406W-tau cases alongside AD, PART, FBD, and FDD in the top branch of the tauopathy tree (image above). Gerstmann-Sträussler-Scheinker disease and prion protein cerebral amyloid angiopathy add two more diseases to this branch. They are caused by different mutations in the prion protein gene and lead to the deposition of prion protein amyloid in the brain parenchyma (GSS) or the vascular compartment (PrP-CAA). Tau inclusions can also feature in both diseases, and in 2021, scientists led by Bernardino Ghetti of Indiana University School of Medicine in Indianapolis reported that tau filaments in both conditions assumed the AD-tau fold (Hallinan et al., 2021).

The AD-tau branch wasn’t the only one to sprout new offshoots. The related CTE-fold, which also features back-to-back Cs, woven of 3R- and 4R-tau as in AD, also got some company. In the first of three studies led by Scheres and Goedert, the CTE fold was found in cases of subacute sclerosing panencephalitis. SSPE is a rare inflammatory condition that can arise in the wake of measles infection (Qi et al., 2023). Months later, they reported the fold in 11 cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC), a fatal neurodegenerative disease of unknown cause, which is found on the island of Guam and on the Kii peninsula of Japan (Qi et al., 2023). It emerged again, when scientists in Japan, along with Scheres and Goedert, investigated a case of vacuolar tauopathy (VT) caused by the D395G mutation in valosin-containing protein (Qi et al., 2024).

In Pick’s disease, a form of frontotemporal dementia cause by a 3R-tauopathy, Scheres and Goedert previously reported that tau twists into an open, J-like configuration (Aug 2018 news). While this fold remains limited to Pick’s, a recent study led by Ghetti and Kathy Newell also at Indiana University, along with Scheres and Goedert, found the fold in two siblings with FTD who carried the DK281 mutation in tau. This allowed them to peg this mutation as a cause of Pick’s (Schweighauser et al., 2023).

Finally, Scheres, Goedert, and Ghetti, collaborating with John van Swieten of Erasmus University in Rotterdam, The Netherlands, added a whole new branch to the tree when they discovered two novel tau twists that formed in carriers of P301L and P301T missense mutations, which cause 4R tauopathies that lead to FTD and globular glial tauopathy (GGT) type III, respectively. The scientists used cryo-EM to resolve tau filaments from five P301L carriers from three unrelated families, and one P301T carrier (Schweighauser et al., 2024).

The same core fold, comprising microtubule binding repeats R2-R4, was found in all five P301L carriers. It formed two layers. One was shorter, because the middle of the R2 domain bulged out to allow flanking residues to line up with R4 amino acids in the longer layer (image below). Except for this R2 kink, this P301L fold resembles the Pick’s fold, which is made of 3R tau and thus lacks the R2 domain. In the P301T case, a structure similar to the P301L two-layer core emerged, although it was not the predominant one. That was yet another tau structure, with a simpler double-layered fold. These new P301L and P301T structures were all woven into fibrils made of single protofilaments. Notably, they differed markedly from those found in sporadic counterparts of FTD and GGT, respectively, suggesting familial forms of these tauopathies were distinct from sporadic ones.

R2 Detour. In five P301L carriers with FTD, the protofilaments formed two layers (left). On one, the R2 domain (blue) bulged out, allowing the remaining R2 residues to form an interface with R3 (green) and R4 (yellow) that resembles the Pick’s fold, which lacks R2. The R4 C-terminus (orange) folds back on itself. Protofilament cores from P301T tauopathies also form a R2-R4 bilayer (right), but without the R2 bulge. [Courtesy of Schweighauser et al., bioRxiv, 2024.]

What does this growing tau tree say about the relationship between tau folds and the tauopathies they cause? The data amassed so far indicate that multiple diseases can have the same fold, but a single disease will never have multiple folds, Scheres and Goedert noted. For example, all AD cases have the AD fold, as do all MAPT-V337M carriers with FTD examined so far.

What instigates a specific fold to form? Scheres and Goedert think that the cellular environment in which tau misfolding first begins may determine what a particular fold will look like. In the case of the AD fold, they believe tau fibrils begin to form not as a response to Aβ amyloidosis, but rather as a function of aging, since the same AD-tau filaments have been found in the entorhinal cortex in cases of primary age-related tauopathy (PART). “The Alzheimer tau fold probably forms as a function of age, but its abundance may be influenced by extracellular deposits, like those of Aβ,” they wrote.

Diamond agreed with that interpretation. “Since PART lacks Aβ pathology, the fact that PART and AD have the same structure suggests that Aβ might play a role in accelerating the progression of tauopathy, rather than simply triggering the AD fibril conformation,” he wrote to Alzforum. 

For the CTE fold, Scheres, Goedert, and Diamond all speculated that it might form in response to specific types of inflammation. Scheres and Goedert added that so far, inclusions of CTE-tau have always been found in the second and third layers of the cortex.

How can different clinical syndromes, such as AD and FTD, arise from the same fold? Scheres and Goedert offered no easy answers to that one. However, this might make development of PET tracers a little easier, since these tend to be conformation-specific, meaning those that work for AD might also work for MAPT-V337M carriers with FTD, as well as people with PART, FBD, and GSS. Tau immunotherapies may be more versatile, since most are not conformation-specific, Scheres and Goedert noted, meaning they might recognize several conformers of tau. However, because antibodies only access the tiny fraction of tau fibrils mingling outside of cells, they favor a blanket tau takedown approach, such as antisense oligonucleotide therapy.

Martin Citron of UCB Biopharma commented that for antibody therapeutics, the importance of tau folds “depends on whether the antibody in question is designed to specifically take out one of the fold forms, and whether these fold forms are actually present in the spreading material, which is currently unknown,” he wrote (comment below).—Jessica Shugart

Comments

1. • Martin Citron
     UCB Pharma Belgium
   • Posted: 28 Mar 2025

   It is important to have structural insights on tau in the different tauopathies and to recognize the differences. Looking at this from a drug discovery perspective, the difference in folds will matter most where molecules need to directly bind to the final folded tau form—a molecule that binds to one form may not bind equally well to a different one. For example, this can explain in part why some tau PET tracers that are good enough for AD are not good enough for PSP. In contrast, for molecules that never interact with different tau folds, such as therapeutics aiming at lowering expression of tau or degrading all tau monomers, the final tau pathology fold should not be critical. For antibody therapeutics, it should depend on whether the antibody in question is designed to specifically take out one of the fold forms and whether these fold forms are actually present in the material that spreads through the brain, which is currently unknown.…More

   View all comments by Martin Citron

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References

News Citations

1. Flock of New Folds Fills in Tauopathy Family Tree 5 Oct 2021
2. Tau Filaments from the Alzheimer’s Brain Revealed at Atomic Resolution 7 Jul 2017
3. Conformers Confirmed: Structure of Pick’s Tau Distinct from AD Tau 31 Aug 2018

Mutations Citations

1. MAPT V337M
2. MAPT R406W
3. MAPT K281del (K280del)
4. MAPT P301L
5. MAPT P301T

Paper Citations

1. Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SH, Goedert M. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. 2021 May;141(5):697-708. Epub 2021 Mar 16 PubMed. Correction.
2. Hallinan GI, Hoq MR, Ghosh M, Vago FS, Fernandez A, Garringer HJ, Vidal R, Jiang W, Ghetti B. Structure of Tau filaments in Prion protein amyloidoses. Acta Neuropathol. 2021 Aug;142(2):227-241. Epub 2021 Jun 14 PubMed.
3. Qi C, Verheijen BM, Kokubo Y, Shi Y, Tetter S, Murzin AG, Nakahara A, Morimoto S, Vermulst M, Sasaki R, Aronica E, Hirokawa Y, Oyanagi K, Kakita A, Ryskeldi-Falcon B, Yoshida M, Hasegawa M, Scheres SH, Goedert M. Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold. Proc Natl Acad Sci U S A. 2023 Dec 19;120(51):e2306767120. Epub 2023 Dec 15 PubMed.
4. Qi C, Kobayashi R, Kawakatsu S, Kametani F, Scheres SH, Goedert M, Hasegawa M. Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G. Acta Neuropathol. 2024 May 17;147(1):86. PubMed.
5. Schweighauser M, Garringer HJ, Klingstedt T, Nilsson KP, Masuda-Suzukake M, Murrell JR, Risacher SL, Vidal R, Scheres SH, Goedert M, Ghetti B, Newell KL. Mutation ∆K281 in MAPT causes Pick's disease. Acta Neuropathol. 2023 Aug;146(2):211-226. Epub 2023 Jun 23 PubMed.
6. Schweighauser M, Shi Y, Murzin AG, Garringer HJ, Vidal R, Murrell JR, Erro ME, Seelaar H, Ferrer I, vanSwieten JC, Ghetti B, Scheres SH, Goedert M. Novel tau filament folds in individuals with MAPT mutations P301L and P301T. 2024 Aug 17 10.1101/2024.08.15.608062 (version 1) bioRxiv.

Further Reading

No Available Further Reading