Neurodegenerative stimuli induce persistent ADF/cofilin–actin rods that disrupt distal neurite function

Abstract

Inclusions containing actin-depolymerizing factor (ADF) and cofilin, abundant proteins in adult human brain, are prominent in hippocampal and cortical neurites of the post-mortem brains of Alzheimer's patients, especially in neurites contacting amyloid deposits. The origin and role of these inclusions in neurodegeneration are, however, unknown. Here we show that mediators of neurodegeneration induce the rapid formation of transient or persistent rod-like inclusions containing ADF/cofilin and actin in axons and dendrites of cultured hippocampal neurons. Rods form spontaneously within neurons overexpressing active ADF/cofilin, suggesting that the activation (by dephosphorylation) of ADF/cofilin that occurs in response to neurodegenerative stimuli is sufficient to induce rod formation. Persistent rods that span the diameter of the neurite disrupt microtubules and cause degeneration of the distal neurite without killing the neuron. These findings suggest a common pathway that can lead to loss of synapses.

Cofilin expression induces cofilin-actin rod formation and disrupts synaptic structure and function in Aplysia synapses

“…It was previously reported that cofilin-actin rods were not labeled with phalloidin, an agent which specifically labels F-actin (11,13). Consistently, fluorescence from Texas red phalloidin did not colocalize with cofilin-GFP (Fig.…”

“…ADF͞cofilin-actin rods are also found in cultured rat hippocampal neurons treated with neurodegenerative stimuli (11). In this case, the neurodegenerative stimuli (e.g., glutamate treatment) appear to induce ADF͞cofilin overactivation and lead to the formation of ADF͞cofilin rods.…”

“…2A). The rod-shaped patterns varied in length (1ϳ20 m), and some of them had cylindrical shape that was similar to cofilin-actin rod found in mammalian systems (11,13,28,29). The expression pattern in cultured pleural mechanosensory neuron was similar to that in other neurons cultured from the central ganglia, although the rod-like structures were relatively shorter (Ͻ10 m), and some of them rather looked punctuated in sensory neurons (Fig.…”

“…Ser-3 of Aplysia cofilin was replaced with Glu to mimic the phosphorylated state of this protein (11). This mutant protein was also fused to GFP to visualize the subcellular localization.…”

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…On the basis of the critical role of actin in the formation of new synapses and the maintenance of synaptic integrity, we hypothesize that overproduction of beta-amyloid (Ab) peptide, by inhibiting dynamic changes in actin polymerization, would lead to neurite retraction and synaptic dysfunction. Neurodegenerative stimuli can induce the formation of actin rods 5 where Ab has been shown to accumulate, and which block transport within neurites 6 . Retracted neurites and disorganized actin filaments are major components of senile plaques and neurofibrillary tangles (NFTs) 7 , which are hallmarks of AD.…”