Amyloid beta from axons and dendrites reduces local spine number and plasticity

Abstract

The amyloid beta (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease. The authors report that overproduction of axonal or dendritic Aβ in rat organotypic slices reduces spine density and plasticity at nearby dendrites. Aβ production is dependent on action potentials and nicotinic receptors, whereas the effects of Aβ are dependent on NMDA receptors. Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Aβ), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Aβ, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Aβ reduced spine density and plasticity at nearby (∼5–10 μm) dendrites. The production of Aβ and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Aβ (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30–60 min blockade of Aβ overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses.