Synaptotoxicity in Alzheimer's Disease Involved a Dysregulation of Actin Cytoskeleton Dynamics through Cofilin 1 Phosphorylation

Abstract

Amyloid-␤ (A␤) drives the synaptic impairment and dendritic spine loss characteristic of Alzheimer's disease (AD), but how A␤ affects the actin cytoskeleton remains unknown and contentious. The actin-binding protein, cofilin-1 (cof1), is a major regulator of actin dynamics in dendritic spines, and is subject to phospho-regulation by multiple pathways, including the Rho-associated protein kinase (ROCK) pathway. While cof1 is implicated as a driver of the synaptotoxicity characteristic of the early phases of AD pathophysiology, questions remain about the molecular mechanisms involved. Cofilin-actin rods are observed in neurons exposed to A␤ oligomers (A␤o) and in tissue from AD patients, and others have described an increased cofilin phosphorylation (p-cof1) in AD patients. Here, we report elevated p-cof1 of the postsynaptic enriched fraction of synaptosomes from cortical samples of male APP/PS1 mice and human AD cases of either sex. In primary cortical neurons, A␤o induced rapid actin stabilization and increased p-cof1 in the postsynaptic compartment of excitatory synapses within 30 min. Fluorescence recovery after photobleaching of actin-GFP and calcium imaging in live neurons expressing active or inactive cof1 mutants suggest that cof1 phosphorylation is necessary and sufficient for A␤o-induced synaptic impairment via actin stabilization before the reported formation of cofilin-actin rods. Moreover, the clinically available and welltolerated ROCK inhibitor, fasudil, prevented A␤o-induced actin stabilization, synaptic impairment, and synaptic loss by blocking cofilin phosphorylation. A␤o also blocked the LTP-induced insertion of the AMPAR subunit, GluA1, at the postsynaptic density, in a fasudilsensitive manner. These data support an important role for ROCKs and cofilin in mediating A␤-induced synaptic impairment.

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

“…In APP/PS1 mice (a mouse model of AD) an increased cofilin activation/dephosphorylation was observed [183,184]. The analysis of the PSD-enriched fraction of both APP/PS1 mice and AD brains revealed a significant increase in cofilin phosphorylation/inactivation in the postsynaptic compartment [185]. Another study showed that cofilin phosphorylation state depends on the stage of the pathology, since an increased activation (dephosphorylation) is detected in APP/PS1 mice brains at four months of age while cofilin is strongly phosphorylated (inactivated) at 10 months of age, corresponding to a full-blown pathology stage [181].…”

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

“…Despite the strong evidence for a role of cofilin activation and oxidation in AD pathogenesis, other studies have shown that cofilin inactivation may also play a role in AD pathogenesis. In the postsynaptic density (PSD) fraction of AD and APP/PS1 mouse brains, phospho-cofilin is increased, and short duration (30 min) A␤ 1-42 oligomer treatment promotes cofilin phosphorylation together with F-actin stabilization in dendritic spines [116], which decreases synaptic plasticity. Another study showed that A␤ oligomers increase cofilin phosphorylation and actin polymerization selectively in basal forebrain cholinergic neurons but not in non-cholinergic neurons via a p75-dependent mechanism [117].…”

Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid

“…Furthermore, ROCK1 and ROCK2 protein abundances are increased among mild cognitive impairment (MCI) and AD patients, implying that ROCKs may contribute to synaptic loss in early disease stages (17,26). Pharmacologic studies with Fasudil and Y-27632, the most widely characterized pan-ROCK inhibitors, suggest beneficial effects of ROCK inhibitors in AD models (27,28). However, these and other ROCK inhibitors are not isoform-specific and can inhibit other AGC family kinases, including protein kinase A (PKA) and protein kinase C (PKC) (29).…”