Soluble β-Amyloid_1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

Abstract

Amyloid-␤ (A␤) 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␤ oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A␤ 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␤ 1-40 reduces PSD-95 protein levels in a dose-and time-dependent manner and that the A␤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␤ 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␤ triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…In addition, the prevention of the decrease in synaptic markers found in treated mice showed that lithium and rosiglitazone prevent synaptic failure found in models of AD. 42,43,74,75 These changes correlate with an enhanced performance in our memory flexibility test, suggesting that hippocampal synaptic function is improved under both treatment conditions.…”

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

“…The attack on synapses inhibits long-term potentiation (LTP) (11,13,14), a classic paradigm for memory-related synaptic mechanisms. ADDL binding further induces AD-like pathology including neuronal tau hyperphosphorylation (15), oxidative stress (16), and synapse deterioration and loss (17)(18)(19)(20)(21). The pathological relevance of ADDLs has been substantiated by their disease-specific accumulation in human brain and CSF (1,22) and by the accumulation of structurally equivalent oligomers in transgenic mouse AD models (23).…”

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

“…Furthermore, the densities of NMDA receptors are decreased (Wakabayashi et al, 1999;Paneggress et al, 2002). Recent studies suggest that glutamate receptors may be involved in Aβ-induced synaptic dysfunction (Snyder et al, 2005;Tyszkiewicz and Yan, 2005;Floden at al., 2005), and soluble Aβ-40 can induce NMDA-dependent degradation of a postsynaptic density-95 protein within glutamatergic synapses (Roselli et al, 2005). In future studies, it would be important to determine whether specific synapse types (glutamatergic versus GABA) are differentially reduced in proximity to β-amyloid plaques.…”