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Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology

Molecular Psychiatry volume 26, pages 5899–5911 (2021)Cite this article

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Abstract

Despite considerable progress in the understanding of its neuropathology, Alzheimer’s disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aβ) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aβ oligomer injection as well as the combined stress and Aβ i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aβ-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aβ-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

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Fig. 1: Allosteric modulation of AMPA receptors by PAM-AMPA compound blocked the cognitive deficits induced by Aβ injection in the hippocampus.
Fig. 2: Prolong modulation of AMPA receptors attenuated the hippocampal-dependent memory impairment of stress/Aβ-exposed animals.
Fig. 3: Modulation of AMPA receptors did not improve the anxious and depressive-like behavior of stress/Aβ-treated animals.
Fig. 4: Prolong modulation of AMPA receptors attenuated stress/Aβ-driven Tau-related excitotoxic synaptic signaling and neurotransmitter reduction.

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Acknowledgements

We thank Drs Luisa Pinto and Patricia Patricio (BnML & ICVS, School of Medicine, University of Minho, Portugal) for their administrative support. In addition, we would like to thank Dr Osborne F.X. Almeida (Max Planck Institute of Psychiatry, Germany) for his critical and constructive comments and feedback on the paper. This work was funded by the Institut de Recherches Internationales Servier (France). Carina Soares-Cunha is holder of a post-doctoral fellowship from the Programa de Atividades Conjuntas (PAC), through MEDPERSYST project (POCI-01-0145-FEDER-016428), supported by the Portugal 2020 Programme Fund (FEDER) while these studies were also supported by the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development.

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Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Campus Gualtar, Minho, Portugal

    Daniela Monteiro-Fernandes, Joana Margarida Silva, Carina Soares-Cunha, Nuno Sousa & Ioannis Sotiropoulos

  2. ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Daniela Monteiro-Fernandes, Joana Margarida Silva, Carina Soares-Cunha, Nuno Sousa & Ioannis Sotiropoulos

  3. Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Christina Dalla & Nikolaos Kokras

  4. First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Nikolaos Kokras

  5. Pôle Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Internationales Servier, Suresnes, France

    François Arnaud, Rodolphe Billiras & Sylvie Bretin

  6. Neurobiology and Behavior Graduate Program, Columbia University, New York, NY, USA

    Viktoriya Zhuravleva

  7. Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Clarissa Waites

  8. Department of Neuroscience, Columbia University, New York, NY, USA

    Clarissa Waites

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  1. Daniela Monteiro-Fernandes
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This study was partly financially supported by the Institut de Recherches Internationales Servier (France) which has no influence on the experimental performance, tissue collection, and analysis as well as data analysis. SB and FA and RB are employees of Institut de Recherches Internationales Servier.

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Monteiro-Fernandes, D., Silva, J.M., Soares-Cunha, C. et al. Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology. Mol Psychiatry 26, 5899–5911 (2021). https://doi.org/10.1038/s41380-020-0794-5

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