Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations

Ineka T. Whiteman, Othon L. Gervasio, Karen M. Cullen, Gilles J. Guillemin, Erica V. Jeong, Paul K. Witting, Shane T. Antao, Laurie S. Minamide, James R. Bamburg, Claire Goldsbury

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Abstract

In Alzheimer's disease (AD), rod-like cofilin aggregates (cofilin-actin rods) and thread-like inclusions containing phosphorylated microtubule- associated protein (pMAP) tau form in the brain (neuropil threads), and the extent of their presence correlates with cognitive decline and disease progression. The assembly mechanism of these respective pathological lesions and the relationship between them is poorly understood, yet vital to understanding the causes of sporadic AD. We demonstrate that, during mitochondrial inhibition, activated actin-depolymerizing factor (ADF)/cofilin assemble into rods along processes of cultured primary neurons that recruit pMAP/tau and mimic neuropil threads. Fluorescence resonance energy transfer analysis revealed colocalization of cofilin-GFP (green fluorescent protein) and pMAP in rods, suggesting their close proximity within a cytoskeletal inclusion complex. The relationship between pMAPand cofilin-actin rods was further investigated using actin-modifying drugs and small interfering RNA knockdown of ADF/cofilin in primary neurons. The results suggest that activation of ADF/cofilin and generation of cofilin-actin rods is required for the subsequent recruitment of pMAP into the inclusions. Additionally, we were able to induce the formation of pMAP-positive ADF/cofilin rods by exposing cells to exogenous amyloid-β (Aβ) peptides. These results reveal a common pathway for pMAP and cofilin accumulation in neuronal processes. The requirement of activated ADF/cofilin for the sequestration of pMAP suggests that neuropil thread structures in the AD brain may be initiated by elevated cofilin activation and F-actin bundling that can be caused by oxidative stress, mitochondrial dysfunction, or Aβ peptides, all suspected initiators of synaptic loss and neurodegeneration in AD.

Original languageEnglish
Pages (from-to)12994-13005
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number41
DOIs
Publication statusPublished - 14 Oct 2009
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2009. Originally published as Whiteman, I. T., Gervasio, O. L., Cullen, K. M., Guillemin, G. J., Jeong, E. V., Witting, P. K., ... & Goldsbury, C. (2009). Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of alzheimer-like neuritic cytoskeletal striations. The Journal of Neuroscience, 29(41), 12994-13005, http://www.jneurosci.org/content/29/41/12994.full.pdf+html. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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