Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer's disease.

Autor: Kim C; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Haldiman T; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Kang SG; Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton T6G 2M8, Canada., Hromadkova L; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Han ZZ; Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton T6G 2M8, Canada., Chen W; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Lissemore F; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Lerner A; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., de Silva R; Reta Lila Weston Institute of Neurological Studies and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1PJ, UK., Cohen ML; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA., Westaway D; Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton T6G 2M8, Canada., Safar JG; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.; Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2022 Jan 05; Vol. 14 (626), pp. eabg0253. Date of Electronic Publication: 2022 Jan 05.
DOI: 10.1126/scitranslmed.abg0253
Abstrakt: 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.
Databáze: MEDLINE