PubMed: 29988016

Inert and seed-competent tau monomers suggest structural origins of aggregation.
Chen D | Colby DW | Diamond MI | Goodarzi M | Joachimiak LA | Liu X | Mirbaha H | Mirzaei H | Morazova OA | Pappu RV | Ruff KM | Sharma AM

Evidence 1ce0ac9977

After 15 min of heparin exposure, we detected low but significant amounts of seed-compe- tent monomer, and much fewer larger assemblies (Figure 6A).

Evidence c4dd29d2fd

Tau from control brain purified in the monomer fraction (Figure 8A), while tau from AD brain distributed across multiple fractions, corresponding to monomer and larger assem- blies (Figure 8B).

Evidence 8fcf055b99

Upon incubation with Lipofectamine, we were surprised to observe seeding by monomer and larger assemblies alike, whether FL WT or 2A. (Figure 1C,D).

Evidence a5d38efd12

AD-derived M s that was purified, frozen, and re-purified by SEC exhibited seeding activ- ity exclusively in the monomer fraction (Figure 8E). By contrast, AD-derived M s incubated at RT formed seed-competent assemblies of increasing size (Figure 8E).

Evidence 51df5b6ba7

However Ms induced amyloid forma- tion, albeit more slowly than trimer or unfractionated fibrils (Figure 1F).

Evidence b0f6cd7ecb

Thus, for our initial studies we engineered and purified full-length (FL) tau monomer that lacks any internal cysteines due to alanine substitu- tions (C299A and C322A), termed tau (2A). FL tau (2A) cannot self-associate based on disulfide link- ages, which helped prevent the formation of cryptic dimers that could have confounded our studies.


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