Cofilin, a Master Node Regulating Cytoskeletal Pathogenesis in Alzheimer’s Disease

Abstract

The defining pathological hallmarks of Alzheimer's disease (AD) are proteinopathies marked by the amyloid-␤ (A␤) peptide and hyperphosphorylated tau. In addition, Hirano bodies and cofilin-actin rods are extensively found in AD brains, both of which are associated with the actin cytoskeleton. The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis. In this review, we discuss the regulation of cofilin by multiple signaling events impinging on LIM kinase-1 (LIMK1) and/or Slingshot homolog-1 (SSH1) downstream of A␤. Such pathophysiological signaling pathways impact actin dynamics to regulate synaptic integrity, mitochondrial translocation of cofilin to promote neurotoxicity, and formation of cofilin-actin pathology. Other intracellular signaling proteins, such as ␤-arrestin, RanBP9, Chronophin, PLD1, and 14-3-3 also impinge on the regulation of cofilin downstream of A␤. Finally, we discuss the role of activated cofilin as a bridge between actin and microtubule dynamics by displacing tau from microtubules, thereby destabilizing tau-induced microtubule assembly, missorting tau, and promoting tauopathy.

Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

“…In the presence of high amounts of ROS, the newly generated F-actin fragments lead to the formation of rods through the direct bundling of these fragments and/or intermolecular disulfide cross-linking of cofilin [172,176]. In summary, the formation of actin rods requires (i) cofilin in the activated (dephosphorylated) form, (ii) cofilin saturation of local regions of F-actin in the presence of abnormally high levels of ADP-actin, which preferentially binds to cofilin, (iii) formation of intermolecular disulfide linkages via oxidation of several key cysteine residues of cofilin [178]. The formation of rods actually may also have a protective function.…”

Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

“…Molecular mechanisms relevant to the neurite and synapse degeneration triggered by amyloid beta (Aβ) and occurring in AD include: increased phosphorylation, misfolding, cleavage and oligomerization of tau 6,7 ; missorting of pathological forms of tau into dendrites and spines promoting deleterious protein-protein interactions 8 ; and aberrant cofilin-mediated actin modification within spines 9 . Upstream signaling changes occurring in AD and likely contributing to these processes include increased tau kinase activity 10 , increased caspase mediated tau cleavage [11][12][13] , and dysregulated Rho kinase activity [14][15][16][17] .…”

Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

“…While the literature suggests that αSyn might impact on neuronal function, through modulation of cofilin-1 activity, is still unclear whether αSyn induces an activation or inactivation of the ABP. Interestingly, a similar scenario was seen in AD where cofilin-1 activity was shown to be regulated in multiple ways depending on the pathogenesis context (Kang and Woo, 2019). Importantly, inhibition of cofilin activity or expression was shown to have ameliorative effects in AD (Deng et al, 2016).…”