Proteopathic tau seeding predicts tauopathy in vivo.

TitleProteopathic tau seeding predicts tauopathy in vivo.
Publication TypeJournal Article
Year of Publication2014
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue41
PaginationE4376-85
Date Published2014 Oct 14
ISSN0027-8424
AbstractTranscellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.
URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=25261551
DOI10.1073/pnas.1411649111
PubMed Linkhttp://www.ncbi.nlm.nih.gov/pubmed/25261551?dopt=Abstract
Short TitleProc Natl Acad Sci U S A