Research Brief: Early Steps in Aβ’s Synaptic Attack
Scientists know that Aβ harms synaptic signaling early in Alzheimer’s disease, but how does the peptide do it? In the May 4 Journal of Neuroscience, researchers led by Dennis Selkoe at Brigham and Women’s Hospital and Harvard Medical School strengthen their previous findings that Aβ oligomers inhibit synaptic long-term potentiation (LTP) by stimulating extrasynaptic NMDA receptors, which kick off harmful signaling cascades. Digging into the mechanism, the researchers found that extrasynaptic stimulation occurs through the buildup of excess extracellular glutamate, rather than through a direct effect of Aβ. The results help clarify the picture of early AD pathology, and also imply that targeting NMDA receptors has the potential to directly modify disease processes.
Selkoe and colleagues previously found that in hippocampal slices from wild-type mice, low, physiological levels of soluble Aβ interfere with glutamate reuptake by the synapse and also activate extrasynaptic NMDA receptors that contain the NR2B subunit (see ARF related news story on Li et al., 2009). It was not clear how Aβ activated these receptors. In the current paper, first authors Shaomin Li and Ming Jin demonstrated that activation is most likely due to excess extracellular glutamate spilling over to these receptors. Using whole-cell patch-clamp recordings, Li and Jin showed that they could mimic the effects of Aβ on synaptic signaling by applying a glutamate reuptake inhibitor to the slice cultures. Conversely, they could rescue LTP from the effects of Aβ by reducing extracellular glutamate with a glutamate scavenger. As in the previous paper, for most experiments, the authors used an Aβ oligomer mixture, mostly consisting of dimers and trimers, secreted by a cell line that expresses mutant human APP. Pure, synthetic Aβ dimers produced similar results, as did Aβ oligomers isolated from human brain.
Selkoe is interested in what Aβ oligomers are binding to on the neuronal cell membrane. Because oligomers are hydrophobic, Selkoe said, “We believe the most likely target would be membrane lipids. Once oligomers are plastered onto the lipid bilayer, they may perturb the function of various transmembrane receptors.” For example, this could be how oligomers inhibit glutamate reuptake by the synapse. To pursue this goal, Selkoe is collaborating with Dominic Walsh, who has moved his laboratory to Harvard from University College Dublin, Ireland. Their goal is to purify oligomers from human brain in sufficient quantities to radiolabel them, and then do binding studies to find their natural partners.
Growing evidence indicates that extrasynaptic NMDA receptors are pathological in a range of neurodegenerative disorders, including ischemic injury and Huntington’s disease, while synaptic NMDA receptors promote neuroprotective pathways (see, e.g., Hardingham and Bading, 2010; Hardingham et al., 2002; Wahl et al., 2009; and ARF related news story on Okamoto et al., 2009). “I think this new paper closes a gap in our knowledge, showing that Aβ in particular engenders a pathological loop centered around extrasynaptic NMDA receptors,” said Stuart Lipton at the University of California in San Diego. Lipton is an author on worldwide patents for memantine, an NMDA receptor antagonist. Extrasynaptic NMDA receptors stimulate neurons to produce pathological Aβ (see Bordji et al., 2010), which then increases extracellular glutamate and further activates these receptors.
This paper implies that targeting extrasynaptic NMDA receptors could modify disease processes, Lipton said. Memantine preferentially affects extrasynaptic sites while sparing synapses (see ARF related news story on Xia et al., 2010), but is not strong enough to slow disease, Lipton said. He added that second-generation drugs are in development. Lipton cautioned that inhibiting NR2B subunits would be a poor strategy, however, because synapses also contain these subunits, raising the possibility of side effects such as sedation and hallucinations. Drug therapy needs to take into account the whole system. “The bottom line is that these things are tied in: Extrasynaptic NMDA receptors, Aβ, and tau will all be critical [if we are] to approach a more disease-modifying treatment,” Lipton told ARF.—Madolyn Bowman Rogers
- Neuronal Glutamate Fuels Aβ-induced LTD
- NMDA Receptors Play Good Cop, Bad Cop in Huntington’s Model
- Common Ground: Is Aβ the Foundation for Multiple Dementias?
- Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PubMed.
- Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010 Oct;11(10):682-96. PubMed.
- Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002 May;5(5):405-14. PubMed.
- Wahl AS, Buchthal B, Rode F, Bomholt SF, Freitag HE, Hardingham GE, Rønn LC, Bading H. Hypoxic/ischemic conditions induce expression of the putative pro-death gene Clca1 via activation of extrasynaptic N-methyl-D-aspartate receptors. Neuroscience. 2009 Jan 12;158(1):344-52. PubMed.
- Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med. 2009 Dec;15(12):1407-13. PubMed.
- Bordji K, Becerril-Ortega J, Nicole O, Buisson A. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production. J Neurosci. 2010 Nov 24;30(47):15927-42. PubMed.
- Xia P, Chen HS, Zhang D, Lipton SA. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010 Aug 18;30(33):11246-50. PubMed.
- Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 2011 May 4;31(18):6627-38. PubMed.
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