Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of alzheimer-like neuritic cytoskeletal striations. The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] Journal article

Title	Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of alzheimer-like neuritic cytoskeletal striations.
Author(s)	Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK, Antao ST, Minamide LS, Bamburg JR, Goldsbury C
Institution	The Brain & Mind Research Institute, and Bosch Institute, School of Medical Sciences, University of Sydney, Camperdown, New South Wales 2006, Australia.
Source	J Neurosci 2009 Oct 14; 29(41):12994-3005.
MeSH	Actin Depolymerizing Factors Actins Adenosine Triphosphate Alzheimer Disease Amino Acid Motifs Amyloid beta-Protein Animals Animals, Newborn Antimycin A Bicyclo Compounds, Heterocyclic Brain Carbonyl Cyanide m-Chlorophenyl Hydrazone Cells, Cultured Chick Embryo Depsipeptides Enzyme Inhibitors Fluorescence Resonance Energy Transfer Green Fluorescent Proteins Humans Hydrogen Peroxide Ionophores Neurites Neurons Organ Culture Techniques Oxidants Peptide Fragments Phosphorylation RNA, Small Interfering Rats Serine Thiazolidines Transfection p21-Activated Kinases tau Proteins
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 pMAP and 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-beta (Abeta) 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 Abeta peptides, all suspected initiators of synaptic loss and neurodegeneration in AD.
Language	eng
Pub Type(s)	In Vitro Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
PubMed ID	19828813

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