Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
- University Grenoble Alpes, France
- Sorbonne Université, France
- Institut du Cerveau et de la Moelle épinière, ICM, France
Abstract
Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington's disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Jean-Christophe Deloulme
Funding
Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)
- Frédéric Saudou
Agence Nationale de la Recherche (ANR-15-IDEX-02 NeuroCoG)
- Frédéric Saudou
Agence Nationale de la Recherche (ANR-10-IAIHU-06)
- Marie-Claude Potier
Fondation pour la Recherche Médicale (DEQ20170336752)
- Sandrine Humbert
Fondation pour la Recherche Médicale (FDT201904008035)
- Hélène Marine Vitet
Fondation pour la Recherche Médicale (DEI20151234418)
- Frédéric Saudou
Fondation pour la Recherche sur le Cerveau
- Frédéric Saudou
INSERM (AGEMED)
- Frédéric Saudou
Fondation Bettencourt Schueller
- Frédéric Saudou
Association Huntington France
- Hélène Marine Vitet
Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)
- Marie-Claude Potier
INSERM (AGEMED)
- Sandrine Humbert
Agence Nationale de la Recherche (ANR-14-CE35-0027-01 PASSAGE)
- Frédéric Saudou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Harry T Orr, University of Minnesota, United States
Ethics
Animal experimentation: Animals were held in accordance with the French Animal Welfare Act and the EU legislation (Council Directive 86/609/EEC) and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. The French Ministry of Agriculture and the local ethics committee gave specific authorization (authorization no. 04594.02) to BD to conduct the experiments described in the present study.
Version history
- Received: February 25, 2020
- Accepted: May 11, 2020
- Accepted Manuscript published: May 26, 2020 (version 1)
- Version of Record published: June 3, 2020 (version 2)
Copyright
© 2020, Bruyère et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
eLife 9:e56371.
https://doi.org/10.7554/eLife.56371
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