UC San Diego

The early stage cognitive deficits in Alzheimer's disease (AD) have been attributed to soluble, oligomeric forms of Amyloid [Beta] (sA[Beta]) and its effect on synaptic structure, function glutamate receptor content. Excitatory synapses in the brain mainly reside on dendritic spines. Their synaptic activity involves ionic currents that are mediated by glutamate receptors. Dendritic spines are rich in the cytoskeletal component actin, which mediates spine stability and morphology as well as anchors receptors to the spine surface. We observe that sA[Beta} reduces the expression of total and surface glutamate receptors through a mechanism that involves an increase in the activity of cofilin, an actin severing protein. In addition, we show that inhibition of cofilin's F-actin severing activity prevents the decrease in surface glutamate receptor expression witnessed in the presence of sA[Beta]. This provides a novel mechanism behind sA[Beta]- induced synaptic dysfunction in Alzheimer's Disease