Soluble β-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses

被引:251
作者
Roselli, F
Tirard, M
Lu, J
Hutzler, P
Lamberti, P
Livrea, P
Morabito, M
Almeida, OFX
机构
[1] Max Planck Inst Psychiat, D-80804 Mainz, Germany
[2] Univ Bari, Dept Neurol & Psychiat Sci, I-70124 Bari, Italy
[3] GSF, Natl Res Ctr Environm & Hlth, Inst Pathol, D-85764 Neuherberg, Germany
[4] Univ Massachusetts, Sch Med, EK Shriver Ctr, Waltham, MA 02452 USA
关键词
phosphorylation; glutamate receptor; metabotropic glutamate receptor; AMPA receptor; synaptic plasticity; amyloid beta; A beta peptide; NMDA receptor; PSD-95; proteasome; cdk5;
D O I
10.1523/JNEUROSCI.3034-05.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyloid-beta(A beta) 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 A beta oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A beta 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 A beta(1 -40) reduces PSD-95 protein levels in a dose- and time- dependent manner and that the A beta 1(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 A beta 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 A beta triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.
引用
收藏
页码:11061 / 11070
页数:10
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