Centaurin-α1-Ras-Elk-1 signaling at mitochondria mediates ß-amyloid-induced synaptic dysfunction.

ABSTRACT

Alzheimer's disease is thought to be caused by ß-amyloid peptide (Aß)-dependent synaptic dysfunction. However, the signaling pathways connecting Aß and synaptic dysfunction remain elusive. Here we report that Aß transiently increases the expression level of centaurin-α1 (CentA1) in neurons, which induces a Ras-dependent association of Elk-1 with mitochondria, leading to mitochondrial and synaptic dysfunction in organotypic hippocampal slices of rats. Downregulation of the CentA1-Ras-Elk-1 pathway restored normal mitochondrial activity, spine structural plasticity, spine density, and the amplitude and frequency of miniature EPSCs in Aß-treated neurons, whereas upregulation of the pathway was sufficient to decrease spine density. Elevations of CentA1 and association of Elk-1 with mitochondria were also observed in transgenic mice overexpressing a human mutant form of amyloid precursor protein. Therefore, the CentA1-Ras-Elk-1 signaling pathway acts on mitochondria to regulate dendritic spine density and synaptic plasticity in response to Aß in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.