Interaction between Ab and a7 nicotinic receptors releases glutamate from astrocytes and produces extrasynaptic NMDAR-mediated synaptic failure: prevention by NitroMemantine

SANZ BLASCO S; TALANTOVA M; ZHANG X; XIA P; AKHTAR MW; OKAMOTO S; DZIEWCZAPOLSKI G; NAKAMURA T; HIRES SA; STOUFFER DG; POWERS ET; KELLY JW; WOLOSKER H; WANG Y; PARSONS LH; HEINEMANN SF; PIÑA-CRESPO JC; LIPTON SA

San Diego

Congreso; Society for Neuroscience 2013; 2013

Society for Neuroscience

Recent failures of clinical trials for Alzheimer?s disease (AD) using anti-amyloid b peptide (Ab) approaches suggest that it may be necessary to target downstream events in the Ab excitotoxic cascade. Since the only neuropathological correlate with cognitive decline in humans with AD is the degree of synaptic loss, we reasoned that protecting synapses might afford a disease-modifying therapy. In this work, we show that soluble oligomeric Ab can engage a7 nicotinic acetylcholine receptors (a7nAChRs) on astrocytes to induce calcium-dependent glutamate release. The resulting extracellular level of glutamate can reach tens of micromolar and activate adjacent neuronal extrasynaptic NMDA receptors (eNMDARs), which leads to both functional and molecular changes heralding synaptic damage. We show that the eNMDAR antagonists memantine and, to a greater degree, NitroMemantine protect synapses from Ab-induced damage both in vitro and in vivo. In the initial experiments, we observed glutamate release from astrocytes after exposure to oligomeric Ab using the FRET-based glutamate sensor SuperGluSnFR (Hires et al., 2008, PNAS, 105:4411-6), which allows detection of local glutamate concentrations with high spatial and temporal resolution. Ab-induced glutamate release was largely reduced in the presence of a-bungarotoxin, a selective a7nAChR antagonist, and in astrocytes lacking a7nAChRs. Additionally, in vivo microdialysis showed higher levels of extracellular glutamate in the hippocampus of mice overexpressing Ab than in littermates lacking a7nAChRs. In vitro experiments revealed that application of Ab oligomers to autaptic hippocampal cultures resulted in eNMDAR-mediated currents and decreased mEPSC frequency (Talantova et al., SfN Abstr 2013). Activation of eNMDARs was followed by increased levels of intracellular Ca2+, NO, activated caspase-3, and phospho-tau, each of which was inhibited by memantine and, more effectively, by NitroMemantine. Experiments on hippocampal slices showed that oligomeric Ab induced synaptic depression and dendritic spine loss that was reversed by these two eNMDAR-preferring antagonists. Importantly, in vivo treatment with NitroMemantine to a far greater degree than memantine was able to protect synapses from damage in Ab-overexpressing transgenic mouse brain. Taken together, our results suggest that Ab-induced synaptic loss may be mediated at least partly by local release of glutamate onto neurons from astrocytes via a7nAChR activation. These findings have therapeutic implications for AD because NitroMemantine, unlike memantine, afforded disease-modification by reversing synaptic loss in a mouse model.