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J Neurosci. 2013 Mar 20;33(12):5367-74. doi: 10.1523/JNEUROSCI.2641-12.2013.

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

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Department of Neurobiology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.


Alzheimer's disease is thought to be caused by β-amyloid peptide (Aβ)-dependent synaptic dysfunction. However, the signaling pathways connecting Aβ and synaptic dysfunction remain elusive. Here we report that Aβ 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 Aβ-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 Aβ in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.

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