Cofilin-Mediated Neurodegeneration in Alzheimer’s Disease and Other Amyloidopathies

Erratum to: Molecular Neurobiology (2007) 35:21–43 DOI 10.1007/BF02700622

Owing to an editing error, uncorrected versions of Figs. 1, 2, and 4 were printed. The correct versions of these figures are reprinted below.

Fig. 1

Proteolytic process of the amyloid precursor protein (APP). (a) Sequential processing of APP by α- and γ-secretases yields a soluble extracellular fragment (sAPPα) and an 83-amino acid transmembrane peptide that is cleaved to yield a soluble P3 fragment and an APP-intracellular domain (AICD), which is targeted to the nucleus. (b) Sequential APP processing by β- and γ-secretases occurs mainly in membrane lipid raft domains and gives rise to a soluble extracellular domain (sAPPβ) and a 99-amino acid transmembrane fragment that is cleaved to yield AICD and the amyloidogenic peptides (Aβ). Variability in the C-terminal cleavage site by γ-secretase gives rise to peptides most commonly either 40 or 42 amino acids in length

Fig. 2

Schematic diagram showing how cofilin enhances actin treadmilling in normal cells and how cofilin-actin rods form in cells under stress. (a) Phosphocycling of cofilin by LIM/TES kinases and slingshot or chronophin phosphatases enhances actin filament turnover and treadmilling. The phosphorylated form of cofilin may be sequestered by 14-3-3 family scaffolding proteins. Active cofilin binds along ADP-actin subunits to promote severing and increased rate of subunit loss from filament (-) ends. The dissociated ADP-actin undergoes nucleotide exchange enhanced by Srv2/Cap1 or profilin and the ATP-actin monomer has low affinity for cofilin, allowing it to recycle back onto the plus end of a growing filament. A rapid hydrolysis of the actin bound ATP to ADP-Pi is followed by the loss of inorganic phosphate. (b) When cells are under stress and ATP levels fall, cofilin undergoes enhanced dephosphorylation and actin exchanges bound ATP for ADP. Cofilin has higher affinity for ADP-actin subunits and binds to them and assembles them into cofilin-saturated ADP-actin filaments. These filaments can bundle to form rods, presumably because of the ability of cofilin to neutralize the negative surface charge on F-actin. Within these rods there is little if any turnover of subunits until ATP levels recover

Fig. 4

Hypothetical model showing possible signaling pathways of fAβ_1–40 and sAβ_1–42 that lead to opposing effects on cofilin activity. APP is cleaved by β- and γ-secretases to produce Aβ within endosomes. Some Aβ assembly may occur before membrane fusion releases soluble species, including monomers, dimers, trimers, and other oligomers into the extracellular space. The binding of sAβ to as yet unidentified receptors may occur at synaptic locations and leads to increased intracellular Ca²⁺, presumably from extracellular sources. Elevated Ca²⁺ can lead to a multiplicity of cellular effects including calcineurin activation, which in turn activates slingshot. Active slingshot can dephosphorylate cofilin, leading to its hyperactivity and, if coupled with ATP reduction, rod formation. Extracellular Aβ also can polymerize into fibrils (fAβ), some of which precipitates to form senile plaques. The activation of integrin receptors by fAβ_1–40 causes recruitment of adhesion proteins and can lead to activation of Rho family GTPases, whose downstream kinases activate LIMK, which inactivates cofilin. Enhanced polymerization and bundling of F-actin in the cell body, growth cones and other lamella ensues, possibly leading to neuritic dystrophy