Glutaredoxin-1 stabilizes A beta mediated F-actin loss and recall memory deficits in Alzheimer’s disease mouse model

Synaptic dysfunction, considered to occur early in AD is often seen as loss of dendritic spines, which are the sites of excitatory signalling in the brain. Fibrillar actin (F-actin) is highly enriched in dendritic spines and determines the shape of spine and undergoes restructuring during synaptic plasticity. We observed reduced levels of F-actin resulting in spine loss and memory deficits in AD mouse model. To understand the molecular mechanisms behind such reduction in F-actin in AD, we analysed the oxidative modifications of actin that affects its polymerization. We observed an increase in glutathionylation as a result of decreased levels of glutaredoxin1 (Grx1), an oxidoreductase enzyme that reduces glutathionylated proteins. This was associated with spine loss and memory deficits. Upon over expressing Grx1, we observed recovery in recall memory deficits, stabilization of F-actin levels and nanoarchitecture in dendritic spines. Our findings suggest that increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD.