Amyloid-β Induces Caspase-Dependent Loss of PSD-95 and Synaptophysin Through NMDA Receptors

Abstract

Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM) and high (10 μM) doses of NMDA, respectively, prevented and potentiated the actions of Aβ. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 μM NMDA, while the effects of 10 μM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was found to mediate the synaptotoxic actions of Aβ in an ifenprodil-reversible fashion. Thus, Aβ leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Aβ initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD.

Liuwei Dihuang decoction facilitates the induction of long-term potentiation (LTP) in senescence accelerated mouse/prone 8 (SAMP8) hippocampal slices by inhibiting voltage-dependent calcium channels (VDCCs) and promoting N-methyl-d-aspartate receptor (NMDA) receptors

“…The expression of NR2A and NR2B is lower in susceptible regions of the AD brain compared to normal controls (Yashiro and Philpot, 2008). A␤ promotes NMDA receptor endocytosis in cultured neurons Roselli et al, 2005;Snyder et al, 2005) and down regulates synaptic proteins by disrupting the function of the NMDA receptor (Liu et al, 2010). Increasing the protein phosphatase 2B (PP2B) activity induced by A␤ can dephosphorylate the tyrosine phosphatase STEP and then promote NR2B trafficking away from the surface .…”

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…It has been suggested that enhancement of GluN2A activity and/or the reduction of GluN2B activity may be used in order to halt the early Aβ-mediated synaptic dysfunction (Liu et al, 2010). Taking into account the importance of ERK for cell survival (described previously in this review), a negative regulation by extrasynaptic NMDARs, mainly composed of GluN2B subunits (Tovar and Westbrook, 1999;Petralia, 2012), may be one of the early signaling events determining brain injury in AD (Ivanov et al, 2006).…”

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…In both AD patients and animal models of this disease, the greastest synapse loss is near senile plaques, indicating a link between Aβ pathology and synaptotoxicity in vivo [7,8] . Furthermore, AβOs have been www.chinaphar.com Zhang LL et al Acta Pharmacologica Sinica npg shown to downregulate the levels of two synaptic proteins, postsynaptic density-95 (PSD-95) and synaptophysin [9] . PSD-95 is an abundant postsynaptic scaffolding protein that plays a critical role in synapse maturation and synaptic plasticity [10] .…”