Amyloid-β1-42 Disrupts Synaptic Plasticity by Altering Glutamate Recycling at the Synapse

Abstract

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorders characterized by neuritic plaques containing amyloid-β peptide (Aβ) and neurofibrillary tangles. Evidence has been reported that Aβ(1-42) plays an essential pathogenic role in decreased spine density, impairment of synaptic plasticity, and neuronal loss with disruption of memory-related synapse function, all associated with AD. Experimentally, Aβ(1-42) oligomers perturb hippocampal long-term potentiation (LTP), an electrophysiological correlate of learning and memory. Aβ was also reported to perturb synaptic glutamate (Glu)-recycling by inhibiting excitatory-amino-acid-transporters. Elevated level of extracellular Glu leads to activation of perisynaptic receptors, including NR2B subunit containing NMDARs. These receptors were shown to induce impaired LTP and enhanced long-term depression and proapoptotic pathways, all central features of AD. In the present study, we investigated the role of Glu-recycling on Aβ(1-42)-induced LTP deficit in the CA1. We found that Aβ-induced LTP damage, which was mimicked by the Glu-reuptake inhibitor TBOA, could be rescued by blocking the NR2B subunit of NMDA receptors. Furthermore, decreasing the level of extracellular Glu using a Glu scavenger also restores TBOA or Aβ induces LTP damage. Overall, these results suggest that reducing ambient Glu in the brain can be protective against Aβ-induced synaptic disruption.

Ginkgolic Acid Protects against Aβ-Induced Synaptic Dysfunction in the Hippocampus

“…It is known that Aβ oligomers are able to perturb hippocampal LTP (Chapman et al, 1999; Chen et al, 2000; Varga et al, 2015) and were also reported to alter synaptic glutamate (Glu)-recycling and transmission (Yao et al, 2013; Varga et al, 2015). Here we wanted to test whether GA exerts a neuroprotective action against Aβ-induced LTP deficiency.…”

“…Also, we investigated the protective effects of GA against Aβ-induced synaptic impairment (Klyubin et al, 2008; Olsen and Sheng, 2012; Yao et al, 2013; Varga et al, 2015). …”

Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system on the inhibition of hippocampal LTP by Aß

“…The inhibition of LTP by Aß is known to require excessive activation of NMDA and mGlu5 receptors (Hu et al, ; Klyubin et al, ; Rammes et al, ; Ronicke et al, ; Hu et al, ) and can be prevented by agents that promote glutamate clearance (Li et al, ; Varga et al, ). Putative sources of excess glutamate triggered by Aß include inhibition of excitatory amino acid transporters, disinhibition of inhibitory neurons and activation of nicotinic acetylcholine receptors on astrocytes to initiate glutamate release (Matos et al, ; Talantova et al, ; Ulrich, ).…”

“…Synaptotoxic Aß can selectively and potently inhibit long‐term potentiation (LTP) of excitatory synaptic transmission (Cullen et al, ; Spires‐Jones and Hyman, ). Reducing glutamate receptor activation with receptor antagonists (Hu et al, ; Klyubin et al, ; Rammes et al, ; Ronicke et al, ; Hu et al, ), or by enhancing glutamate clearance (Li et al, ; Takahashi et al, ; Varga et al, ; Zumkehr et al, ) has been reported to block the disruption of synaptic plasticity by Aß.…”

Aβ and the dementia syndrome: Simple versus complex perspectives

“…Cognitive function ultimately depends on synaptic plasticity where long‐term potentiation (LTP) is associated with synapse growth and long‐term depression (LTD) is associated with synapse loss. Biomedical mechanistic experimental design based on the amyloid cascade hypothesis often measures changes to LTP or LTD to represent the neurotoxicity of Aβ, for example . In contrast, the APP matrix approach suggests that dynamic balance within the APP proteolytic system as a whole is involved in the regulation of synaptic plasticity.…”