title: Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity.
abstract: Microglia, macrophage-like resident immune cells in the brain, possess both neurotoxic and neuroprotective properties and have a critical role in the development of Alzheimer's disease (AD). We examined the function of Interleukin-34 (IL-34), a newly discovered cytokine, on microglia because it reportedly induces proliferation of monocytes and macrophages. We observed that the neuronal cells primarily produce IL-34 and that microglia express its receptor, colony-stimulating factor 1 receptor. IL-34 promoted microglial proliferation and clearance of soluble oligomeric amyloid-β (oAβ), which mediates synaptic dysfunction and neuronal damage in AD. IL-34 increased the expression of insulin-degrading enzyme, aiding the clearance of oAβ, and induced the antioxidant enzyme heme oxygenase-1 in microglia to reduce oxidative stress, without producing neurotoxic molecules. Consequently, microglia treated with IL-34 attenuated oAβ neurotoxicity in primary neuron-microglia co-cultures. In vivo, intracerebroventricular administration of IL-34 ameliorated impairment of associative learning and reduced oAβ levels through up-regulation of insulin-degrading enzyme and heme oxygenase-1 in an APP/PS1 transgenic mouse model of AD. These findings support the idea that enhancement of the neuroprotective property of microglia by IL-34 may be an effective approach against oAβ neurotoxicity in AD.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. tmizuno@riem.nagoya-u.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Doi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.forename: Mariko
authors.initials: M
authors.lastname: Noda
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sonobe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D007339:Insulysin / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007858:Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D007378:Interleukins; D018696:Neuroprotective Agents; C552364:interleukin-34, mouse; D051547:Heme Oxygenase-1; D007339:Insulysin