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The alpha7 nicotinic acetylcholine receptor mediates network dysfunction in a mouse model of local amyloid pathology

Molecular Psychiatry (2025)Cite this article

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Abstract

Patient and animal model data suggest a link between the cholinergic neuromodulatory system and the amyloid beta (Aβ) peptide in causing Alzheimer’s disease (AD). But how cholinergic dysfunctions contribute to AD pathology remains controversial. In a mouse model of local amyloid pathology, we show that in the early disease stages, the α7 nicotinic acetylcholine receptor (nAChR) is an important target of Aβ in the prefrontal cortex (PFC). Using in vivo two-photon calcium imaging and in vivo patch-clamp electrophysiology in the PFC of awake mice, we demonstrate that Aβ-mediated disruption of specifically the α7 nAChR subunit, expressed by distinct interneuron subtypes, results in substantial deficits in network activity. This is corroborated by electrophysiology experiments in slices. Combined with computational modeling, we propose that α7 nAChRs are occluded by Aβ early in the disease, whereas the heteropentameric α5 and β2 nAChRs are only partially inactivated and potentially provide novel therapeutic targets for intervention. Accordingly, we show that galantamine, an approved acetylcholine-esterase inhibitor (AChE-I), which acts as a positive allosteric modulator (PAM) of α5-containing nAChRs at low concentrations, reduces neuronal hyperactivity.

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Fig. 1: Expression of human APP has no effect on PYR neuron activity in layer 2/3 of PrLC in α7KO mice.
Fig. 2: Human Aβ oligomers increase the activity of PV INs.
Fig. 3: Increased membrane potential fluctuations and hyperactivity in PFC PYR neurons in vivo after AAV-hAPP injection.
Fig. 4: Inhibition of α7 nAChRs in vivo mimics the effect of Aβ-induced hyperactivity in PFC PYR.
Fig. 5: α7 nAChRs are occluded in WT-APP mice.
Fig. 6: Human Aβ oligomers differentially inactivate distinct nAChRs during the disease progression.
Fig. 7: Galantamine reduces PYR neuron activity early in AD.

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Data availability

The data and analysis algorithms are available. The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

The data and analysis algorithms are available.

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Acknowledgements

We would like to thank Noémi Dominique for technical assistance, Matthias Groszer and Florent Haiss for comments on the manuscript, and Ines Ibanez-Tallon for providing the ChAT-Cre transgenic mice. This work was supported by the Fondation pour la Recherche Médicale (FRM Équipe 2019, grant number EQU201903007822), Fondation Vaincre Alzheimer, Fondation Alzheimer-INSERM, Institut Pasteur programme PasteurInnov, CNRS UMR3571, Programme prioritaire TABAC-INSERM, all to U.M., ERC Starting Grant NEWRON to C.S.-H., and the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907, Human Brain Project SGA2 and Specific Grant Agreement No. 720270, Human Brain Project SGA1 (to J.-P.C: CDP6, Modeling Drug Discovery). B.S.G. and I.L. acknowledge support from the Basic Science Fund NRU Higher School of Economics, and received partial support from LABEX ANR-10-LABX-0087 IEC and IDEX ANR-10-IDEX-0001-02 PSL*. The laboratory of U.M. is part of the RTRA Ecole des Neurosciences de Paris ENP network. U.M. is a member of the Laboratory of Excellence LABEX BIOPSY, funded by Agence Nationale de la Recherche. The authors acknowledge the team from the animal facility of BioMedTech Facilities INSERM US36|CNRS UAR2009 | Université Paris Cité. The team of F.K. acknowledges support from the Fondation pour la Recherche Médicale-FRM Amorçage de jeunes équipes 2022 (starting grant number AJE202212016251) and the ATIP-AVENIR starting grant 2023 (INSERM/ French National Institute of Health and Medical Research), all to F.K. Finally, the authors would like to thank Philippe Ascher for his participation in the initial electrophysiology recordings of this paper.

Author information

Author notes

  1. These authors contributed equally: Fani Koukouli, Chun-Lei Zhang.

Authors and Affiliations

  1. Institut Pasteur, Université de Paris Cité, Integrative Neurobiology of Cholinergic Systems, Department of Neuroscience, CNRS, UMR 3571, Paris, France

    Fani Koukouli, Daniela Gaspar Santos, Stéphanie Pons, Jérémy Peixoto, Camille Thiberge & Uwe Maskos

  2. Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm U1127, CNRS, UMR 7225, Paris, France

    Fani Koukouli & Alberto Bacci

  3. Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Cholinergic modulation of cortical inhibitory circuits in health and disease group, Paris, France

    Fani Koukouli & Ifigeneia Nikolakopoulou

  4. GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France

    Fani Koukouli & Ifigeneia Nikolakopoulou

  5. Institut Pasteur, Université de Paris Cité, Neural circuits for spatial navigation and memory, Department of Neuroscience, Paris, France

    Chun-Lei Zhang & Christoph Schmidt-Hieber

  6. École Normale Supérieure, Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unité 969, Département d’Études Cognitives, Paris, France

    Ivan Lazarevich, Marie Rooy & Boris S. Gutkin

  7. Center for Cognition and Decision Making, Institute for Cognitive Neuroscience, National Research University Higher School of Economics, Moscow, Russia

    Ivan Lazarevich & Boris S. Gutkin

  8. Université de Paris Cité, SPPIN - Saints-Pères Paris Institute for the Neurosciences, CNRS, UMR 8003, Paris, France

    Boris Lamotte d’Incamps

  9. Institut Pasteur, Université de Paris Cité, Department of Neuroscience, CNRS, UMR 3571, Paris, France

    Jean-Pierre Changeux

  10. Collège de France, Paris, France

    Jean-Pierre Changeux

  11. Institute for Physiology I – Neurophysiology, Jena University hospital, Jena, Germany

    Christoph Schmidt-Hieber

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  13. Boris S. Gutkin
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  14. Christoph Schmidt-Hieber
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  15. Uwe Maskos
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Contributions

FK and CZ carried out in vivo analysis, IL and MR carried out two-photon data analysis and modeling with BG, BLd’I and JP carried out slice electrophysiology, DGS and SP established experimental groups and carried out histological analysis, CT and IN contributed to histology, UM and FK conceived the study, UM, FK, CZ, CS-H, BLd’I and AB designed experiments, UM and FK wrote the paper with contributions from all authors, UM, CS-H and J-PC provided funding.

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Correspondence to Christoph Schmidt-Hieber or Uwe Maskos.

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Koukouli, F., Zhang, CL., Lazarevich, I. et al. The alpha7 nicotinic acetylcholine receptor mediates network dysfunction in a mouse model of local amyloid pathology. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03241-4

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