title: 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.
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Talantova
authors.forename: Sara
authors.initials: S
authors.lastname: Sanz-Blasco
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Mohd Waseem
authors.initials: MW
authors.lastname: Akhtar
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Okamoto
authors.forename: Gustavo
authors.initials: G
authors.lastname: Dziewczapolski
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Gang
authors.initials: G
authors.lastname: Cao
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Pratt
authors.forename: Yeon-Joo
authors.initials: YJ
authors.lastname: Kang
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
authors.forename: Elena
authors.initials: E
authors.lastname: Molokanova
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.forename: Samuel Andrew
authors.initials: SA
authors.lastname: Hires
authors.forename: Hagit
authors.initials: H
authors.lastname: Sason
authors.forename: David G
authors.initials: DG
authors.lastname: Stouffer
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Buczynski
authors.forename: James P
authors.initials: JP
authors.lastname: Solomon
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Amanda
authors.initials: A
authors.lastname: Roberts
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: Traci
authors.initials: T
authors.lastname: Fang-Newmeyer
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.forename: Emily A
authors.initials: EA
authors.lastname: Holland
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: H-S Vincent
authors.initials: HS
authors.lastname: Chen
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: Juan C
authors.initials: JC
authors.lastname: Piña-Crespo
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D018698:Glutamic Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid
keywords: astrocytes; glutamate receptors; α7-nicotinics