The Role of ADF/Cofilin in Synaptic Physiology and Alzheimer’s Disease

Abstract

Actin-depolymerization factor (ADF)/cofilin, a family of actin-binding proteins, are critical for the regulation of actin reorganization in response to various signals. Accumulating evidence indicates that ADF/cofilin also play important roles in neuronal structure and function, including long-term potentiation and depression. These are the most extensively studied forms of long-lasting synaptic plasticity and are widely regarded as cellular mechanisms underlying learning and memory. ADF/cofilin regulate synaptic function through their effects on dendritic spines and the trafficking of glutamate receptors, the principal mediator of excitatory synaptic transmission in vertebrates. Regulation of ADF/cofilin involves various signaling pathways converging on LIM domain kinases and slingshot phosphatases, which phosphorylate/inactivate and dephosphorylate/activate ADF/cofilin, respectively. Actin-depolymerization factor/cofilin activity is also regulated by other actin-binding proteins, activity-dependent subcellular distribution and protein translation. Abnormalities in ADF/cofilin have been associated with several neurodegenerative disorders such as Alzheimer’s disease. Therefore, investigating the roles of ADF/cofilin in the brain is not only important for understanding the fundamental processes governing neuronal structure and function, but also may provide potential therapeutic strategies to treat brain disorders.

The molecular view of mechanical stress of brain cells, local translation, and neurodegenerative diseases

“…Its rearrangements by rapid assembly of actin monomers (G actin) to filaments (F actin) and inverse disassembly are essential for the formation of synaptic plasticity and long-term memory (Penzes, Rafalovich, 2012;Basu, Lamprecht, 2018). Disturbances in the mechanisms regulating the formation of F actin filaments and dendritic spine structure are thought to be associated with neurodegenerative disorders: Alzheimer's disease, schizophrenia, and autism (Bamburg, Bernstein, 2016;Borovac et al, 2018;Forrest et al, 2018;Ben Zablah et al, 2020;Lauterborn et al, 2020). Fig.…”

Overexpression of LIMK1 in hippocampal excitatory neurons improves synaptic plasticity and social recognition memory in APP/PS1 mice

“…Together with cofilin phosphatases, LIMK1 regulates the balance of phosphorylated (inactive) and dephosphorylated (active) cofilin to control actin reorganization [20,21]. Perturbations of LIMK1 and cofilin have been shown to impair spine morphology, synaptic plasticity and memory, underscoring the crucial role of LIMK1/ cofilin signaling in synaptic and brain function [22][23][24][25]. Recent studies have also shown that abnormalities in both LIMK1 and cofilin are associated with AD patients and animal models of AD [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

“…Perturbations of LIMK1 and cofilin have been shown to impair spine morphology, synaptic plasticity and memory, underscoring the crucial role of LIMK1/ cofilin signaling in synaptic and brain function [22][23][24][25]. Recent studies have also shown that abnormalities in both LIMK1 and cofilin are associated with AD patients and animal models of AD [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. For example, the level of phosphorylated cofilin was found to be decreased by the Aβ treatment as well as in the brain of AD mouse models [25,[28][29][30][31][32][33][34][35][36][37][38], suggesting that overactivation of cofilin may contribute to AD pathology.…”

“…Recent studies have also shown that abnormalities in both LIMK1 and cofilin are associated with AD patients and animal models of AD [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. For example, the level of phosphorylated cofilin was found to be decreased by the Aβ treatment as well as in the brain of AD mouse models [25,[28][29][30][31][32][33][34][35][36][37][38], suggesting that overactivation of cofilin may contribute to AD pathology. Interestingly, increased phosphorylated cofilin (i.e., decreased cofilin activity) has also been found to be associated with AD models under some circumstances [25,[29][30][31][32][33].…”

“…For example, the level of phosphorylated cofilin was found to be decreased by the Aβ treatment as well as in the brain of AD mouse models [25,[28][29][30][31][32][33][34][35][36][37][38], suggesting that overactivation of cofilin may contribute to AD pathology. Interestingly, increased phosphorylated cofilin (i.e., decreased cofilin activity) has also been found to be associated with AD models under some circumstances [25,[29][30][31][32][33]. These results indicate complex effects of AD pathology on LIMK1/cofilin signaling, and therefore, whether and how LIMK1/cofilin contributes to AD pathogenesis remains unclear.…”