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Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation

Molecular Psychiatry volume 23, pages 1530–1540 (2018)Cite this article

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Abstract

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer’s disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

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Acknowledgements

We thank Dr Flint Beal and Ms Shari Jainuddin for providing the PS19 model; Dr Rakez Kayed for providing the T22 antibody; Dr Magali Dumont for her help in the animal protocol preparation; Dr Benoit Delatour and Dr Ihsen Youssef for helping with mouse perfusions; Dr Annick Prigent and the ICM histology facility team for helping with the cytochrome oxidase staining; and Dr Lydia Danglot for the Icy software training. In vivo studies were performed at the PHENO-ICMice Core Facility with the help of Dr Nadège Sarrazin, Dr Magali Dumont and Ms Béatrice Moreau; the Core is supported by the ‘Investissements d'avenir’ ANR-10- IAIHU-06 and ANR-11-INBS-0011-NeurATRIS, and by the ‘Fondation pour la Recherche Médicale’. CIBERNED and grants from the Ministerio de Economía y Competitividad (SAF2013-45084-R), Govierno Vasco, Ikerbasque and Universidad del País Vasco UPV/EHU to EC, EA and CM. This study was possible by the support of Institut Professeur Baulieu to YA and DT.

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Author notes

  1. E Gondard, A Mann, T Vaccari and A M Lozano: These authors contributed equally to this work.

  2. D Tampellini: Lead contact.

Authors and Affiliations

  1. U 1195 INSERM—Université Paris Sud—Université Paris-Saclay, Le Kremlin-Bicêtre, France

    Y Akwa, E E Baulieu & D Tampellini

  2. Department of Neurosurgery, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada

    E Gondard, A Mann & A M Lozano

  3. Departamento de Neurociencias, Achucarro Basque Center for Neuroscience, Universidad del. País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain

    E Capetillo-Zarate, E Alberdi & C Matute

  4. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    E Capetillo-Zarate

  5. Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA

    E Capetillo-Zarate

  6. Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Université Pierre et Marie Curie, GH Pitié-Salpêtrière, Paris, France

    S Marty

  7. IFOM—FIRC Institute of Molecular Oncology and Dipartimento di Bioscienze, Universita’ degli Studi di Milano, Milan, Italy

    T Vaccari

  8. Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada

    A M Lozano

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  1. Y Akwa
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Akwa, Y., Gondard, E., Mann, A. et al. Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation. Mol Psychiatry 23, 1530–1540 (2018). https://doi.org/10.1038/mp.2017.142

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