Amyloid precursor protein combinatorial phosphorylation code regulates AMPA receptor removal during distinct forms of synaptic plasticity

• Published in: Biochemical and biophysical research communications 2024-05, Vol.709, p.149803, Article 149803
• Main Authors: Lee, Jisoo, Pak, Daniel T.S.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; AMPA receptor; Amyloid beta-Protein Precursor - metabolism; APP; GluA2; Homeostatic plasticity; Humans; LTD; Neuronal Plasticity - physiology; Phosphorylation; Plk2; Receptors, AMPA - metabolism; Serine - metabolism; Synapses - metabolism; Threonine - metabolism
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.149803

Synaptic plasticity is essential for memory encoding and stabilization of neural network activity. Plasticity is impaired in neurodegenerative conditions including Alzheimer disease (AD). A central factor in AD is amyloid precursor protein (APP). Previous studies have suggested APP involvement in synaptic plasticity, but physiological roles of APP are not well understood. Here, we identified combinatorial phosphorylation sites within APP that regulate AMPA receptor trafficking during different forms of synaptic plasticity. Dual phosphorylation sites at threonine-668/serine-675 of APP promoted endocytosis of the GluA2 subunit of AMPA receptors during homeostatic synaptic plasticity. APP was also required for GluA2 internalization during NMDA receptor-dependent long-term depression, albeit via a distinct pair of phosphoresidues at serine-655/threonine-686. These data implicate APP as a central gate for AMPA receptor internalization during distinct forms of plasticity, unlocked by specific combinations of phosphoresidues, and suggest that APP may serve broad functions in learning and memory. •Amyloid precursor protein (APP) phosphorylation sites regulate AMPA receptor trafficking.•Dual phospho sites (T668/S675) of APP promoted removal of surface GluA2 AMPA receptors during homeostatic plasticity.•Distinct pair of phosphosites (S655/T686) in APP was required for GluA2 loss during NMDA-dependent long-term depression.•APP cytosolic phosphosites were not required for mGluR or AMPA-dependent GluA2 removal.•Combinatorial APP phosphorylation is a central gate for AMPA receptor removal in distinct forms of synaptic plasticity.