Oxidative Stress Mediated Loss of Synaptosomal F-Actin Occurs Prior to Onset of Pathophysiological Hallmarks of Alzheimer's Disease

Synaptic dysfunction is considered to occur prior to the appearance of the pathophysiological and behavioural symptoms of Alzheimer’s disease (AD). Dendritic spine loss is seen in AD and precedes the cognitive dysfunction in mouse model of AD; however the molecular mechanisms are poorly understood. Fibrillar actin (F-actin) is the major cytoskeleton protein in dendrites and is very important for defining dendritic spine morphology. We measured dendritic F-actin levels, in vitro, in primary cortical neurons and found that dendritic F-actin levels are significantly decreased in neurons from APP/PS1 Tg mice. We also measured F-actin and globular-actin (G-actin; monomer) expression, in vivo, in synaptosomes derived from the cortices of wild-type (WT) and APP/PS1 Tg mice during adolescence (1 month) and middle age (9 months). We found significant decrease in F-actin levels in the synaptosomes from adolescent APP/PS1 Tg mice and this reduction was sustained until middle age. F-actin levels are unaffected in post-nuclear supernatant across the ages examined. Further, we observed loss of reduced F-actin but not reduced G-actin in the synaptosomes of APP/PS1 Tg mice compared to age matched WT mice. Synaptosomal actin-S-glutathionylation, which is known to hinder F-actin polymerization, was significantly increased in adolescent APP/PS1 Tg mice. This observation was replicated in human postmortem brain tissue, wherein we observed significant reduction of F-actin in synaptosomes isolated from human subjects with AD dementia. Significant correlation was seen between decrease in synaptosomal F-actin and poor performance in memory and other cognitive tasks in samples from normal controls, MCI (mild cognitive impairment) and AD indicating that loss of F-actin may contribute to the disease process in humans. These findings delineate that the loss of F-actin through oxidative modification at the synapse plays a critical role in synaptic dysfunction in AD pathogenesis.