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

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.