title: Granulocyte-colony stimulating factor attenuates oligomeric amyloid β neurotoxicity by activation of neprilysin.
abstract: Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Yukiko
authors: Y
authors: Doi
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Hideyuki
authors: H
authors: Takeuchi
authors: Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Hiroyuki
authors: H
authors: Mizoguchi
authors: Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Kazuya
authors: K
authors: Fukumoto
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Hiroshi
authors: H
authors: Horiuchi
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Shijie
authors: S
authors: Jin
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Jun
authors: J
authors: Kawanokuchi
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Bijay
authors: B
authors: Parajuli
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Yoshifumi
authors: Y
authors: Sonobe
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Tetsuya
authors: T
authors: Mizuno
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors: Akio
authors: A
authors: Suzumura
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D016179:Granulocyte Colony-Stimulating Factor; D015244:Thiorphan; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; D015260:Neprilysin