التفاصيل البيبلوغرافية
| العنوان: |
Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation. |
| المؤلفون: |
Davis, Richard C.1, Marsden, Ian T.1, Maloney, Michael T.1,2, Minamide, Laurie S.1, Podlisny, Marcia3, Selkoe, Dennis J.3, Bamburg, James R.1 jbamburg@lamar.colostate.edu |
| المصدر: |
Molecular Neurodegeneration. 2011, Vol. 6 Issue 1, p10-26. 17p. |
| مصطلحات موضوعية: |
*OLIGOMERS, *PHOSPHORYLATION, *NEURONS, *TYROSINE, *AMINO acids |
| مستخلص: |
Background: 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. Results: Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Ab dimers and trimers (Aβd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Ab oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ1-42, 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 Aβd/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 Ab monomers are not active, suggesting oxidized SDS-stable Aβ1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/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 Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Conclusions: Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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