Role of LIMK1-cofilin-actin axis in dendritic spine dynamics in Alzheimer's disease

Abstract

Dysregulation of dendritic spine dynamics, a process essential for synaptic plasticity and memory, is a hallmark of Alzheimer's disease (AD). Actin dynamics, largely regulated by the LIMK1-cofilin pathway, are central to maintaining structural and functional stability in neurons. In healthy brains, the LIMK1-cofilin-actin axis modulates actin polymerization within dendritic spines, supporting spine growth and plasticity. However, in AD, this pathway is altered, leading to both actin and synaptic dysfunction. Studies report conflicting findings, with some indicating LIMK1 hyperactivation leading to cofilin inactivation, while others observe elevated cofilin activity, suggesting divergent regulatory mechanisms depending on the disease stage or neuronal environment. The paradoxical effects of LIMK1-cofilin signaling in AD may result from a context-dependent regulation influenced by factors such as amyloid-beta (Aβ) and tau protein accumulation, which disrupt actin dynamics and promote synaptic degeneration. The presence of cofilin-actin rods and Hirano bodies in AD highlights the role of aberrant actin stabilization and its impact on neurodegenerative processes. This review synthesizes current findings on LIMK1-cofilin-actin signaling in AD, emphasizing the dual role of cofilin in stabilizing and severing actin filaments. Targeting the LIMK1-cofilin-actin axis presents a promising therapeutic approach to restore dendritic spine dynamics and mitigate cognitive decline. However, resolving inconsistencies in cofilin regulation is essential to developing effective treatments for AD.

Fig. 1. Synaptic and structural plasticity in healthy and AD neurons.

A Pathway diagram of canonical signaling involved in structural plasticity of dendritic spines. In AD, this pathway is disrupted, leading to compromised synaptic and structural plasticity (modified from Ripoli et al. [90]). B Illustration of a healthy neuron and its spine density. Dendritic spine schematic representation on the right shows high spine density and synaptic growth during LTP in healthy neurons, indicating robust structural plasticity. C Cartoon of an AD neuron and its reduced spine density compared with A. The presence of amyloid-β (Aβ) protein and tau oligomers is depicted, which contributes to impaired structural plasticity of dendritic spines, leading to diminished synaptic connections and plasticity. Created with BioRender.com.

Fig. 2. Mechanisms of cofilin regulation and its role in actin dynamics through LIMK1-mediated Ser3 phosphorylation.

A Cartoon representation of a kinase interacting with a substrate. The kinase engages with the substrate through distal docking and a linear motif, leading to phosphorylation (P) of the substrate. B Cartoon of LIMK1 interacting with cofilin. LIMK1 phosphorylates cofilin at Ser3 in the absence of a linear motif, highlighting the peculiarity of its activity. A, B Modified from Hamil et al. [39]. C Schematic diagram of cofilin regulation and its impact on actin dynamics. Active cofilin (unphosphorylated) promotes actin severing. Phosphorylation by LIMK1 inactivates cofilin, leading to actin polymerization (highlighted in yellow) and enhanced structural plasticity. SSH1 dephosphorylates cofilin, restoring its actin-severing activity. Created with BioRender.com.

Fig. 3. Cofilin-mediated actin polymerization governs the structural plasticity of dendritic spines.

Modulation of actin polymerization within dendritic spines through the activity of cofilin. On the left, active cofilin (in red) facilitates the severing and depolymerization of F-actin (blue filaments), releasing G-actin monomers (blue spheres). At rest, a balance between two opposing processes, actin polymerization and cofilin activity, maintains the structure of the spine. AMPAR and NMDAR receptors are illustrated on the synaptic membrane. The right panel shows the transition where LIMK1 phosphorylates cofilin, making it inactive, thereby allowing actin polymerization (highlighted in yellow) to promote the expansion of the dendritic spines, essential for structural changes associated with volume enlargement and the corresponding increase in the number of AMPAR. Created with BioRender.com.

Fig. 4. Impaired actin dynamics in Alzheimer’s disease (AD) neurons mediated by amyloid-beta (Aβ) and tau pathology.

Cartoon depicting an AD neuron and the impact of Aβ and tau oligomers on LIMK1-cofilin-actin axis in AD spines. Activated LIMK1 phosphorylates ADF/cofilin, leading to the inhibition of its actin-severing activity. Altered actin dynamics result from excessive activation or inhibition of this pathway. The increased cofilin phosphorylation observed in AD may initially act as a compensatory mechanism to restore disrupted actin polymerization. However, persistent dysregulation of the LIMK1-cofilin axis over time can exacerbate synaptic impairment and contribute to further cognitive decline.