Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau

The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the...

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Published in:The Journal of neuroscience 2016-01, Vol.36 (3), p.762-772
Main Authors: Jackson, Samuel J, Kerridge, Caroline, Cooper, Jane, Cavallini, Annalisa, Falcon, Benjamin, Cella, Claire V, Landi, Alessia, Szekeres, Philip G, Murray, Tracey K, Ahmed, Zeshan, Goedert, Michel, Hutton, Michael, O'Neill, Michael J, Bose, Suchira
Format: Article
Language:English
Subjects:
Amyloid - genetics
Animals
Brain - pathology
Female
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurofibrillary Tangles - genetics
Neurofibrillary Tangles - pathology
tau Proteins - genetics
Tauopathies - genetics
Tauopathies - pathology
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Summary:The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the cycle. At present, it is not known which tau species are seed-competent. Here, we have dissected the molecular characteristics of seed-competent tau species from the TgP301S tau mouse model using various biochemical techniques and assessed their seeding ability in cell and animal models. We found that sucrose gradient fractions from brain lysates seeded cellular tau aggregation only when large (>10 mer) aggregated, hyperphosphorylated (AT8- and AT100-positive) and nitrated tau was present. In contrast, there was no detectable seeding by fractions containing small, oligomeric (
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.3542-15.2016