title: Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits. Amyloidogenic processing of amyloid precursor protein (APP) produces amyloid β (Aβ), the major component of hallmark AD plaques. Synaptic activity stimulates APP cleavage, whereas APP promotes excitatory synaptic transmission, suggesting APP participates in neuronal homeostasis. However, mechanisms linking synaptic activity to APP processing are unclear. Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in vitro and associates with APP in vivo. Plk2 accelerates APP amyloidogenic cleavage by β-secretase at synapses and is required for neuronal overactivity-stimulated Aβ secretion. These findings implicate Plk2 as a novel mediator of activity-dependent APP amyloidogenic processing.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007-2126, USA; Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul, 02841, South Korea.
authors.forename: Yeunkum
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007-2126, USA.
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007-2126, USA; Research Division, Korea Brain Research Institute, Daegu 700-010, Republic of Korea.
authors.forename: Kea Joo
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Department of Neurology, Georgetown University Medical Center, Washington, DC 20007-2126, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Turner
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007-2126, USA; Research Division, Korea Brain Research Institute, Daegu 700-010, Republic of Korea.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007-2126, USA. Electronic address: Daniel.Pak@georgetown.edu.
authors.forename: Daniel T S
authors.initials: DTS
authors.lastname: Pak
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D013569:Synapses / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D017346:Protein Serine-Threonine Kinases
keywords: Alzheimer's disease; Amyloidogenic processing; Hyperexcitation; Neurodegeneration; Neuronal signaling; Polo-like kinase 2; Synaptic plasticity