Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 50; pp. E8187 - E8196
• Main Authors: Woerman, Amanda L., Aoyagi, Atsushi, Patel, Smita, Kazmi, Sabeen A., Lobach, Iryna, Grinberg, Lea T., McKee, Ann C., Seeley, William W., Olson, Steven H., Prusiner, Stanley B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-12-2016
• Series: PNAS Plus
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological Sciences; Brain; Cell Line; Cells; Chronic Traumatic Encephalopathy - genetics; Chronic Traumatic Encephalopathy - metabolism; HEK293 Cells; Humans; Luminescent Proteins - chemistry; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mutation; Pick Disease of the Brain - genetics; Pick Disease of the Brain - metabolism; PNAS Plus; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Supranuclear Palsy, Progressive - genetics; Supranuclear Palsy, Progressive - metabolism; tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; Up-Regulation; tauopathies; corticobasal degeneration; argyrophilic grain disease; Pick’s disease; progressive supranuclear palsy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1616344113

Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer’s disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R- or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.