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

Lee, Yeunkum; Lee, Ji Soo; Lee, Kea Joo; Turner, R. Scott; Hoe, Hyang‐Sook; Pak, Daniel T.S.

doi:10.1016/j.neuropharm.2017.02.027

Cited by 25 publications

(33 citation statements)

References 49 publications

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“…S675 is another serine residue that has been detected to be phosphorylated in the brains of AD patients, but its function was only recently clarified. Lee et al reported that Polo-like kinase 2 (Plk2) is able to phosphorylate both T668 and S675 residues [64]. Plk2 is sensitive to neuronal activity and plays a role in regulating synaptic function.…”

Section: App Phosphorylationmentioning

confidence: 99%

“…The overactivation of neurons, such as that which occurs in the presence of Aβ oligomers, induces the expression of Plk2 at somatodendrites, wherein the kinase directly interacts with the intracellular domain of APP and phosphorylates the T668 and S675 residues. Phosphorylation stimulates the endocytosis of APP and drives the BACE1 mediated cleavage, thereby increasing the production of Aβ in the synapse [64]. By using a phospho-mimicking protein of APP, Menon et al showed that S675 phosphorylation increases the noncanonical APP processing by meprin β but decreases the α-secretase cleavage at the plasma membrane.…”

Section: App Phosphorylationmentioning

confidence: 99%

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Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

Zhang

Chen

Lee

2019

IJMS

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The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer's disease (AD). The regulation of the processing of the single-transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.

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Section: App Phosphorylationmentioning

confidence: 99%

Section: App Phosphorylationmentioning

confidence: 99%

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

Zhang

Chen

Lee

2019

IJMS

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“…Several lines of evidence indicate that Aβ oligomer levels are markedly elevated in the brains of AD patients and in AD mouse models expressing human-mutant amyloid precursor protein (APP) [9,10] and that these elevated levels trigger synaptic degeneration at the level of dendritic spines [11,12], which are tiny membrane protrusions that receive most of the excitatory inputs in the brain [13]. It has also been suggested that excessive neuronal activity related to stress or seizures promotes Aβ production in the brain [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in Alzheimer’s disease

Jang

Kim

et al. 2020

Preprint

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Background: Excessive neuronal activity promotes amyloid-β (Aβ) production in the brain. The Aβ oligomer triggers synaptic degeneration that precedes plaque and tangle pathology. However, the signaling molecules that link Aβ oligomers to synaptic pathology remain unclear. RAPGEF2, a guanine-nucleotide exchange factor for the small GTPase Rap, plays a role in activity-dependent synapse remodeling and is involved in the pathogenesis of epilepsy commonly observed in Alzheimer’s disease (AD) patients and mouse models. Thus, we postulated that the perturbation of the RAPGEF2 signal may contribute to Aβ oligomer-induced synaptopathy in AD. Methods: To investigate the potential role of RAPGEF2 in Aβ oligomer-induced synaptic and cognitive impairments in AD, we utilized a combination of approaches including biochemistry, molecular cell biology, light and electron microscopy, behavioral tests with primary neuron cultures, multiple AD mouse models and postmortem human AD brain tissue. Results: We observed significantly elevated RAPGEF2 levels in the postmortem human AD hippocampus. RAPGEF2 levels also increased in the transgenic AD mouse models, generating high levels of Aβ oligomers before exhibiting synaptic and cognitive impairment. RAPGEF2 upregulation activated its downstream effectors Rap2 and JNK. In cultured hippocampal neurons, oligomeric Aβ treatment increased the fluorescence intensity of RAPGEF2 and reduced the number of dendritic spines, while silencing RAPGEF2 expression blocked Aβ oligomer-induced spine loss. Additionally, the in vivo knockdown of RAPGEF2 expression in the AD hippocampus prevented cognitive deficits and the loss of excitatory synapses. Conclusions: These findings demonstrate that the upregulation of RAPGEF2 levels mediates Aβ oligomer-induced synaptic and cognitive disturbances in the AD hippocampus. We propose that early intervention regarding RAPGEF2 expression may have beneficial effects on early synaptic pathology and memory loss in AD.

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“…APP and Aβ may have an important role in this homeostatic plasticity (Lee et al . ). When Aβ is produced during strong synaptic activity, its accumulation and the removal of full‐length APP could together act over time to reduce local synaptic numbers and strength, thus regulating the overall activity of the neuron.…”

mentioning

confidence: 97%

“…While productive synaptic connections are strengthened via long-term potentiation processes, counteracting effects are induced to prevent neuronal overactivity. APP and Ab may have an important role in this homeostatic plasticity (Lee et al 2017). When Ab is produced during strong synaptic activity, its accumulation and the removal of fulllength APP could together act over time to reduce local synaptic numbers and strength, thus regulating the overall activity of the neuron.…”

mentioning

confidence: 99%