Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer’s disease
Shape matters
The accumulation of TAU protein aggregates is one of the major hallmarks of Alzheimer’s disease (AD). Although TAU accumulation has been shown to be a predictor of cognitive decline in patients with AD, the correlation between AD progression and TAU remains to be elucidated. Here, Kim et al. isolated and analyzed TAU protein structure obtained from patients with different disease progression and showed an association between progression rate and distinct TAU conformers. Rapidly progressing AD was associated with mostly misfolded four-repeat (4R) TAU and high replication rate in vitro. The results suggest that the structure of TAU protein aggregates should be considered when developing potential treatment for slowing or halting AD progression.
Abstract
Although genetic factors play a main role in determining the risk of developing Alzheimer’s disease (AD), they do not explain extensive spectrum of clinicopathological phenotypes. Deposits of aggregated TAU proteins are one of the main predictors of cognitive decline in AD. We investigated the hypothesis that variabilities in AD progression could be due to diverse structural assemblies (strains) of TAU protein. Using sensitive biophysical methods in 40 patients with AD and markedly different disease durations, we identified populations of distinct TAU particles that differed in size, structural organization, and replication rate in vitro and in cell assay. The rapidly replicating, distinctly misfolded TAU conformers found in rapidly progressive AD were composed of ~80% misfolded four-repeat (4R) TAU and ~20% of misfolded 3R TAU isoform with the same conformational signatures. These biophysical observations suggest that distinctly misfolded population of 4R TAU conformers drive the rapid decline in AD and imply that effective therapeutic strategies might need to consider not a singular species but a cloud of differently misfolded TAU conformers.
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Science Translational Medicine
Volume 14 | Issue 626
January 2022
January 2022
Copyright
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 7 December 2020
Accepted: 6 November 2021
Acknowledgments
We are grateful to the patients’ families, the CJD Foundation, referring physicians, and all the members of the CWRU Alzheimer’s Disease Center and National Prion Disease Pathology Surveillance Center for technical help and review of data. We are indebted to E. Gelpi, S. Borrego-Ecija, L. Molina-Porcel, and T. Ximelis of the Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Barcelona, Spain for FTLD MAPT P301L and Pick’s disease sample and data procurement and to all brain donors and their families for brain donation for research. We are grateful to A. Miron for Illumina and Sanger sequencing, W. Surewicz for K18 and K19 plasmids, and E. Poptic for scaled-up production of RD3 antibody.
Funding: Work in the Safar laboratory was supported by grants from BrightFocus Foundation (A2016085S), Alberta Innovates Biosolutions (FP00209618), and NIH (1RF1AG058267 and 1RF1AG061797). Westaway laboratory was funded by a Canada Research Chair (tier 1), CIHR (PS148962 and GER 163048), and Alberta Innovates Biosolutions (ABIBS AEP 201600021 and 20160023). The NACC database is funded by NIA grant U01 AG016976.
Author contributions: J.G.S. and D.W. conceived the study. M.L.C. performed diagnostic neuropathology. A.L. and F.L. collected, processed, and interpreted clinical data. C.K. conducted conformational and sucrose gradient analyses. T.H. expressed and purified recombinant K18 and K19 TAU proteins and performed seeding assays. W.C. performed prion protein analyses and immunohistochemistry. J.G.S., C.K., T.H., L.H., and D.W. designed the experiments and interpreted and prepared the data for publication. J.G.S. wrote the paper, and all authors were involved in reviewing, refining, and approving the final version of the manuscript.
Competing interests: The authors declare that they have no competing financial interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials.
Authors
Funding Information
National Institutes of Health: 1RF1AG058267 and 1RF1AG061797
National Institutes of Health: 1RF1AG058267
National Institutes of Health: 1RF1AG061797
National Institute on Aging: AG016976
National Institute on Aging: U01 AG016976
BrightFocus Foundation: A2016085S
BrightFocus Foundation: A2016085S
Alberta Innovates Biosolutions: FP00209618
Canadian Institutes of Health Research: PS148962
Canadian Institutes of Health Research: GER 163048
Alberta Innovates Biosolutions: ABIBS AEP 201600021
Alberta Innovates Biosolutions: 20160023
Case Western Reserve University: FTLD MAPT P301L
Alberta Innovates Biosolutions: FP00209618
Alberta Innovates Biosolutions: 201600021 and 20160023
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