Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin

• Published in: eLife Vol. 9
• Main Authors: Bruyère, Julie, Abada, Yah-Se, Vitet, Hélène, Fontaine, Gaëlle, Deloulme, Jean-Christophe, Cès, Aurélia, Denarier, Eric, Pernet-Gallay, Karin, Andrieux, Annie, Humbert, Sandrine, Potier, Marie-Claude, Delatour, Benoît, Saudou, Frédéric
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 26.05.2020; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: AKT protein; alzheimer disease; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Anterograde transport; Axonal Transport; Axons; Brain - diagnostic imaging; Cell Biology; Dendrites; Disease Models, Animal; Homeostasis; Huntingtin; Huntingtin Protein - metabolism; Huntingtons disease; Life Sciences; Localization; Magnetic Resonance Imaging; Male; Memory; Mice, Transgenic; Microfluidic Analytical Techniques; Microfluidics; Morris Water Maze Test; Neuroscience; Phosphorylation; Physiology; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; synapse; Synapses - metabolism; Synaptic density; alzheimer disease; mouse; cell biology; amyloid precursor protein; huntingtin; neuroscience; synapse
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.56371

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.