UMMS Affiliation
Department of Cell Biology
Publication Date
2005-12-02
Document Type
Article
Subjects
Amyloid beta-Peptides; Animals; Calcium; Cell Membrane; Cells, Cultured; Cyclin-Dependent Kinase 5; Down-Regulation; Frontal Lobe; Glutamic Acid; Humans; Intracellular Signaling Peptides and Proteins; inhibitors; Membrane Proteins; N-Methylaspartate; Nerve Tissue Proteins; Neurons; Peptide Fragments; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Solubility; Synapses
Disciplines
Cell Biology
Abstract
Amyloid-beta (Abeta) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble Abeta oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of Abeta in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of Abeta(1-40) reduces PSD-95 protein levels in a dose- and time-dependent manner and that the Abeta1(1-40)-dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that Abeta treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which Abeta triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.
DOI of Published Version
10.1523/JNEUROSCI.3034-05.2005
Source
J Neurosci. 2005 Nov 30;25(48):11061-70. Link to article on publisher's site
Journal/Book/Conference Title
The Journal of neuroscience : the official journal of the Society for Neuroscience
Related Resources
PubMed ID
16319306
Repository Citation
Roselli, F.; Tirard, M.; Lu, J.; Hutzler, P.; Lamberti, P.; Livrea, P.; Morabito, Maria A.; and Almeida, O.F.X., "Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses" (2005). Morabito Lab Publications. 1.
https://escholarship.umassmed.edu/morabito/1