Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing

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...

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Bibliographic Details
Published in:Neuropharmacology 2017-05, Vol.117, p.387-400
Main Authors: Lee, Yeunkum, Lee, Ji Soo, Lee, Kea Joo, Turner, R. Scott, Hoe, Hyang-Sook, Pak, Daniel T.S.
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Amyloidogenic processing
Animals
Chlorocebus aethiops
COS Cells
Hippocampus - metabolism
Humans
Hyperexcitation
Mice, Inbred C57BL
Mice, Knockout
Neurodegeneration
Neuronal signaling
Neurons - metabolism
Phosphorylation
Polo-like kinase 2
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases - metabolism
Rats
Synapses - metabolism
Synaptic plasticity
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Summary: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. [Display omitted] •Only N-terminal antibodies recognize postsynaptic pools of APP in cultured neurons.•Plk2 is required for activity-dependent β-site processing of synaptic APP.•Plk2 interacts directly with and phosphorylates APP at Ser675 and Thr688.•APP dual phosphorylation by Plk2 regulates its surface expression and β-processing.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2017.02.027