Could New Glutamate Receptor Activators Treat Alzheimer’s?

According to an article in the January 14 Cell Reports, boosting the activity of certain excitatory receptors in the brain calms epileptic activity and improves learning and memory in mouse models of disease. Jesse Hanson, Genentech Inc. in South San Francisco, and Jorge Palop, Gladstone Institute of Neurological Disease, San Francisco, report that the positive allosteric modulator GNE-0723 lowers abnormal oscillations in neural networks. GNE-0723 is an experimental compound that selectively boosts the activity of N-methyl-D-aspartate receptors containing GluN2A subunits. It’s too soon to test it in people, the researchers write. For now, it can lead to a better understanding of how NMDAR function affects circuits in the normal and diseased brain. “This is the first time we have tested the effects of GluN2A-positive allosteric modulators in vivo,” Hanson wrote to Alzforum.

  • Scientists test a positive allosteric modulator of GluN2ANMDA receptor.
  • The compound reduces epileptiform activity in mice.
  • It also boosts learning and memory.

NMDA receptors are heterotetrameric ion channels that open in response to glutamate. At synapses, NMDARs contain GluN2A subunits; at other sites along the neuronal cell membrane, they tend to favor GluN2B. Scientists have capitalized on this to develop positive allosteric modulators (PAMs) to enhance either synaptic or extrasynaptic NMDAR function (Hackos et al., 2016). The receptors have been linked to Aβ toxicity in Alzheimer’s and to seizures in AD and in epilepsy (May 2011 news; Sep 2007 news). 

Researchers at Genentech recently developed GNE-0723, a small molecule that selectively enhances GluN2A function, thus boosting synaptic NMDAR signaling. The researchers tested this PAM in mouse models of Alzheimer’s and Dravet syndrome, a type of epilepsy. In both conditions, inhibitory interneurons flounder, leading to too much synchronized neuronal activity.

Co-first authors Hanson, Justin Elstrott, and Martin Weber at Genentech, along with Sandrine Saillet and Keran Ma at UCSF, first applied GNE-0723 to brain slices from wild-type mice. The compound increased NMDAR excitatory postsynaptic currents in both excitatory pyramidal neurons and inhibitory interneurons. In the J20 mouse model of amyloidosis and in the Scn1a-KI model of Dravet syndrome, it reduced abnormal low-frequency oscillations and epileptiform bursts detected by EEG. After five weeks on GNE-0723, treated J20 and wild-type mice remembered the location of a hidden platform in the Morris water maze better than untreated controls. GNE-0723-treated Scn1a-KI mice froze more in anticipation of a foot shock than vehicle-treated controls.

NMDAR PAMs could help treat conditions that involve hyperexcitable networks, such as epilepsy and AD, the authors wrote. However, GNE-0723’s ability to improve memory in wild-type mice suggests it does not work by suppressing epileptic activity alone.

For now, Genentech regards PAMs as research tools. They plan to test another one, GNE-5729. It functions similarly but apparently has better pharmacokinetic properties.

Researchers at Emory University School of Medicine in Atlanta have also developed a series of NMDAR PAMs that allow passage of Na+ into the cell but restrict Ca2+, lowering the possibility of excitotoxicity (Perszyk et al., 2020).—Gwyneth Dickey Zakaib

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References

News Citations

  1. Research Brief: Early Steps in Aβ’s Synaptic Attack
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)

Paper Citations

  1. Hackos DH, Lupardus PJ, Grand T, Chen Y, Wang TM, Reynen P, Gustafson A, Wallweber HJ, Volgraf M, Sellers BD, Schwarz JB, Paoletti P, Sheng M, Zhou Q, Hanson JE. Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function. Neuron. 2016 Mar 2;89(5):983-99. Epub 2016 Feb 11 PubMed.
  2. Perszyk RE, Swanger SA, Shelley C, Khatri A, Fernandez-Cuervo G, Epplin MP, Zhang J, Le P, Bülow P, Garnier-Amblard E, Gangireddy PK, Bassell GJ, Yuan H, Menaldino DS, Liotta DC, Liebeskind LS, Traynelis SF. Biased modulators of NMDA receptors control channel opening and ion selectivity. Nat Chem Biol. 2020 Jan 20; PubMed.

Further Reading

Papers

  1. Song X, Jensen MØ, Jogini V, Stein RA, Lee CH, Mchaourab HS, Shaw DE, Gouaux E. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature. 2018 Apr;556(7702):515-519. Epub 2018 Apr 18 PubMed.
  2. Wang R, Reddy PH. Role of Glutamate and NMDA Receptors in Alzheimer's Disease. J Alzheimers Dis. 2016 Sep 23; PubMed.
  3. Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer's disease. Neurol Sci. 2016 Jul;37(7):1039-47. Epub 2016 Mar 12 PubMed.
  4. Yao L, Zhou Q. Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators. Neural Plast. 2017;2017:2875904. Epub 2017 Jan 9 PubMed.

Primary Papers

  1. Hanson JE, Ma K, Elstrott J, Weber M, Saillet S, Khan AS, Simms J, Liu B, Kim TA, Yu GQ, Chen Y, Wang TM, Jiang Z, Liederer BM, Deshmukh G, Solanoy H, Chan C, Sellers BD, Volgraf M, Schwarz JB, Hackos DH, Weimer RM, Sheng M, Gill TM, Scearce-Levie K, Palop JJ. GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models. Cell Rep. 2020 Jan 14;30(2):381-396.e4. PubMed.
  2. Perszyk RE, Swanger SA, Shelley C, Khatri A, Fernandez-Cuervo G, Epplin MP, Zhang J, Le P, Bülow P, Garnier-Amblard E, Gangireddy PK, Bassell GJ, Yuan H, Menaldino DS, Liotta DC, Liebeskind LS, Traynelis SF. Biased modulators of NMDA receptors control channel opening and ion selectivity. Nat Chem Biol. 2020 Jan 20; PubMed.

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