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Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model

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Abstract

Alzheimer’s disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short (“stubby”) spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines and the width of spine necks are inversely correlated with synapse density in frontal cortical biopsies from non-AD and AD patients. In mice, the reduction in the density of synapses in the stratum radiatum was preceded by an alteration of spine morphology, with a reduction of their length and an enlargement of their neck. Serial sectioning examined with electron microscopy allowed us to precisely measure spine parameters. Mathematical modeling indicated that the shortening and widening of the necks should alter the electrical compartmentalization of the spines, leading to reduced postsynaptic potentials in spine heads, but not in soma. Accordingly, there was no alteration in basal synaptic transmission, but long-term potentiation and spatial memory were impaired. These results indicate that an alteration of spine morphology could be involved in the early cognitive deficits associated with AD.

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Acknowledgements

We are grateful to Prof. Jean-François Foncin for having established a collection of biopsies taken during neurosurgery (Profs. Le Beau and Philippon) and having provided it to us, and for critical reading of the manuscript. We thank Pascal Barneoud and Laurent Pradier from Sanofi for sharing the APPxPS1-KI mouse line and for stimulating discussions. We also thank Patricia Bassereau for helpful discussions, and Laura Xicota for help with statistics. Serge Marty and Alexandre Androuin were supported by a grant from France Alzheimer. The present work was also supported by funding from the program Investissements d’avenir ANR-10-IAIHU-06, ANR-11-INBS-0011-NeurATRIS and the Fondation pour la Recherche Médicale. Antoine Triller was supported by Grants from Association France Alzheimer (Project R12035JJ), the Agence Nationale de la Recherche (ANR-09-MNPS-013-01 and ANR-11-BSV8-021-01), the ERC advanced research grant ‘PlasltInhib’, and the program “Investissements d’Avenir” (ANR-10-LABX-54 MEMO LIFE and ANR-11-IDEX-0001-02 PSL* Research University). We also thank the imaging facility of the IBENS and the imaging facility icm.Quant of the ICM, particularly Dominique Langui and Asha Baskaran for the electron microscopy. This work was partly carried out on the ICM vectorology platform with the help of André Sobczyk, and HISTOMICS platform with the help of Annick Prigent. We also thank the biostatistics facility of the ICM and particularly François-Xavier Lejeune. All animal work was conducted at the ICM PHENOPARC Core Facility. We thank Magali Dumont, Nadège Sarrazin, Delphine Roussel, and Joanna Droesbeke from the PHENO.ICMice for their help.

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Author notes

  1. Brigitte Potier

    Present address: Biophotonique et Réseaux Neuronaux, UMR9188 LAC, Université Paris-Sud, Orsay, France

  2. Alexandre Androuin and Brigitte Potier are co-first authors.

  3. Benoît Delatour and Serge Marty are co-last authors.

Authors and Affiliations

  1. Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France

    Alexandre Androuin, Manon Thierry, Ihsen Youssef, Charles Duyckaerts, Khalid Hamid El Hachimi, Benoît Delatour & Serge Marty

  2. Centre de Psychiatrie et Neurosciences, INSERM, UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Brigitte Potier, Lydia Danglot & Patrick Dutar

  3. Biophotonique et Réseaux Neuronaux, UMR9188 LAC, Université Paris-Sud, Orsay, France

    Patrick Dutar

  4. Institut Interdisciplinaire de Neurosciences, CNRS UMR 5297, Bordeaux, France

    U. Valentin Nägerl

  5. Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS UMR 5287, Bordeaux, France

    Daniel Cattaert

  6. Université de Bordeaux, Bordeaux, France

    U. Valentin Nägerl & Daniel Cattaert

  7. École Normale Supérieure, Institut de Biologie de l’ENS, INSERM, CNRS, PSL Research University, Paris, France

    Antoine Triller

  8. Laboratoire de Neurogénétique, EPHE, PSL Research University, Paris, France

    Khalid Hamid El Hachimi

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  1. Alexandre Androuin
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Androuin, A., Potier, B., Nägerl, U.V. et al. Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model. Acta Neuropathol 135, 839–854 (2018). https://doi.org/10.1007/s00401-018-1847-6

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