Iwatsubo, Takeshi

Publication Detail

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Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation.

Richard C Davis; Ian T Marsden; Michael T Maloney; Laurie S Minamide; Marcia Podlisny; Dennis J Selkoe; James R Bamburg (Profiled Author: Selkoe, Dennis J)

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA. jbamburg@lamar.colostate.edu.
Molecular neurodegeneration 2011;6():10.

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 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 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 Aβ 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.

2 Originating Grant

• 1.

  SELKOE, DENNIS J

  Aging in the Brain: The Role of the Fibrous Proteins

  1 September 1985 - 30 April 2012

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 6,982,031

• 2.

  SELKOE, DENNIS J

  Aging in the Brain: Role of the Fibrous Proteins

  1 September 1985 - 30 April 2017

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 2,223,247

Scientific Context

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