Centaurin-α1-Ras-Elk-1 Signaling at Mitochondria Mediates β-Amyloid-Induced Synaptic Dysfunction

Alzheimer's disease is thought to be caused by beta-amyloid peptide (A beta)-dependent synaptic dysfunction. However, the signaling pathways connecting A beta and synaptic dysfunction remain elusive. Here we report that A beta transiently increases the expression level of centaurin-alpha 1 (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 A beta-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 A beta in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.