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Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation.
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ABSTRACT: Background
Previously we reported 1 ?M synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus.Results
Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human A? dimers and trimers (A?d/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human A? oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent A?1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 A?d/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing A? monomers are not active, suggesting oxidized SDS-stable A?1-42 dimers in a low-n state are the most active rod-inducing species. A?d/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after A?d/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with A?d/t, whereas overexpression of a cofilin kinase inhibits A?d/t-induced rod formation.Conclusions
Together these data support a mechanism by which A?d/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.
SUBMITTER: Davis RC
PROVIDER: S-EPMC3037337 | biostudies-literature | 2011 Jan
REPOSITORIES: biostudies-literature
Publications
Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation.
Molecular neurodegeneration 20110124
<h4>Background</h4>Previously we reported 1 μM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus.<h4>Results</h4>Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ o ...[more]