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Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Abstract：

:Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Talantova M,Sanz-Blasco S,Zhang X,Xia P,Akhtar MW,Okamoto S,Dziewczapolski G,Nakamura T,Cao G,Pratt AE,Kang YJ,Tu S,Molokanova E,McKercher SR,Hires SA,Sason H,Stouffer DG,Buczynski MW,Solomon JP,Michael S,Powers E

doi

10.1073/pnas.1306832110

subject

Has Abstract

pub_date

2013-07-02 00:00:00

pages

E2518-27

issue

27

eissn

0027-8424

issn

1091-6490

pii

1306832110

journal_volume

110

pub_type

杂志文章

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