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PubMed: 29988016

Title
Inert and seed-competent tau monomers suggest structural origins of aggregation.
Journal
eLife
Volume
7
Issue
None
Pages
None
Date
2018-07-10
Authors
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
JSON

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

a(CHEBI:heparin) increases p(HGNC:MAPT, var("?")) View Subject | View Object

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a(CHEBI:heparin) increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence c4dd29d2fd
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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).

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 8fcf055b99
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Upon incubation with Lipofectamine, we were surprised to observe seeding by monomer and larger assemblies alike, whether FL WT or 2A. (Figure 1C,D).

a(PUBCHEM:100984821) increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence a5d38efd12
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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).

p(HGNC:MAPT) increases a(HBP:"Tau aggregates") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence 51df5b6ba7
JSON

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

p(HGNC:MAPT, var("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence b0f6cd7ecb
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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.

p(HGNC:MAPT, var("p.Cys299Ala"), var("p.Cys322Ala")) decreases complex(p(HGNC:MAPT), p(HGNC:MAPT)) View Subject | View Object

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