TY - JOUR TI - Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin AU - Bruyère, Julie AU - Abada, Yah-Se AU - Vitet, Hélène AU - Fontaine, Gaëlle AU - Deloulme, Jean-Christophe AU - Cès, Aurélia AU - Denarier, Eric AU - Pernet-Gallay, Karin AU - Andrieux, Annie AU - Humbert, Sandrine AU - Potier, Marie-Claude AU - Delatour, Benoît AU - Saudou, Frédéric A2 - Orr, Harry T A2 - Zoghbi, Huda Y VL - 9 PY - 2020 DA - 2020/05/26 SP - e56371 C1 - eLife 2020;9:e56371 DO - 10.7554/eLife.56371 UR - https://doi.org/10.7554/eLife.56371 AB - 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. KW - alzheimer disease KW - huntingtin KW - amyloid precursor protein KW - synapse JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -