ausblenden:
Schlagwörter:
Alzheimer Disease/*metabolism/pathology, Amyloid beta-Peptides/*metabolism, Animals, Cells, Cultured, Dendritic Spines/metabolism/pathology, ets-Domain Protein Elk-1/*metabolism, Excitatory Postsynaptic Potentials/physiology, GTPase-Activating Proteins/*metabolism, Hippocampus/cytology, Humans, Male, MAP Kinase Signaling System/*physiology, Mice, Mice, Inbred Strains, Mice, Transgenic, Mitochondria/metabolism, Nerve Tissue Proteins/*metabolism, Neuronal Plasticity/physiology, Neurons/cytology/physiology, ras Proteins/*metabolism, Rats, Rats, Sprague-Dawley
Zusammenfassung:
Alzheimer's disease is thought to be caused by beta-amyloid peptide (Abeta)-dependent synaptic dysfunction. However, the signaling pathways connecting Abeta and synaptic dysfunction remain elusive. Here we report that Abeta transiently increases the expression level of centaurin-alpha1 (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 Abeta-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 Abeta in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.
