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Huntingtin protein regulates Amyloid-Precursor Protein homeostasis.

on the July 1, 2020
figureWeb_saudou.png
Amyloid precursor protein (APP), when mutated is associated with familial forms of Alzheimer’s disease. 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.

In collaboration with the Delatour and Potier group at the Institut du Cerveau in Paris, we showed that 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.

 

Legend:
Huntingtin regulates APP trafficking, modulates synaptic density and restores memory in mouse models of familial forms of Alzheimer's disease.
Modeling the corticocortical circuitry on microfluidic chips (left) allows to visualize the transport of APP in axons and the formation of synapses that are regulated by huntingtin phosphorylation (HTTSA). Loss of synaptic contact in the presence of APP (APPmCherry) is restored in the absence of HTT phosphorylation (HTTSA). In vivo, the absence of phosphorylation restores the number and size of synapses and memory in APPPS1 mice.
 
 
Reference:
Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin. Bruyère J, Abada YS, Vitet H, Fontaine G, Deloulme JC, Cès A, Denarier E, Pernet-Gallay K, Andrieux A, Humbert S, Potier MC, Delatour B, Saudou F. Elife. 2020 May 26;9:e56371. doi: 10.7554/eLife.56371. PMID: 32452382

Updated on July 2, 2020

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