Loss of synaptic structure and function is thought to mark early stages of Alzheimer's disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. was partly supported by a Vigoni grant (Conferenza dei Rettori delle Università Italiane, CRUI, Roma, Italy and the German Academic Exchange Service), the University of Bari (Italy), and the Max Planck Institute of Psychiatry (Munich, Germany). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: F.R. Received: DecemAccepted: Published: June 23, 2009Ĭopyright: © 2009 Roselli et al. PLoS ONE 4(6):Įditor: Hitoshi Okazawa, Tokyo Medical and Dental University, Japan In summary, soluble Aβ recruits discrete signalling pathways to rapidly reduce the synaptic localization of major components of the PSD and to regulate the availability of mGluR1 in the synapse.Ĭitation: Roselli F, Hutzler P, Wegerich Y, Livrea P, Almeida OFX (2009) Disassembly of Shank and Homer Synaptic Clusters Is Driven by Soluble β-Amyloid 1-40 through Divergent NMDAR-Dependent Signalling Pathways. The regulation of Homer1b and Shank1 by Aβ diverges in two other respects: i) whereas the activity of both NMDAR and VDCC is required for Aβ-induced declustering of Homer1b, Aβ-induced declustering of Shank1 only requires NMDAR activity and ii) whereas the effects of Aβ on Homer1b involve engagement of the PI-3K pathway and calcineurin phosphatase (PP2B) activity, those on Shank1 involve activation of the ERK pathway. We show that de novo protein synthesis is required for the declustering effects of Aβ on Homer1b (but not Shank1) and that, in contrast to PSD-95, Aβ-induced Homer1b and Shank1 cluster disassembly does not depend on proteasome activity. Treatment of fronto-cortical neurons with soluble Aβ results in rapid (within 1 h) and significant thinning of the PSD, decreased synaptic levels of Homer1b and Shank1, and reduced synaptic mGluR1 levels.
Extending our previous demonstration that derangement of the PSD by soluble amyloid-β (Aβ) involves proteasomal degradation of PSD-95, a protein important for ionotropic glutamate receptor trafficking, we now show that Aβ also disrupts two other scaffold proteins, Homer1b and Shank1, that couple PSD-95 with ionotropic and metabotropic glutamate receptors. Disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines, is thought to be responsible for synaptic dysfunction and loss in early-stage Alzheimer's disease (AD).
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