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-␤ (oA␤), which mediates synaptic dysfunction and neuronal damage in AD. IL-34 increased the expression of insulin-degrading enzyme, aiding the clearance of oA␤, 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 oA␤ neurotoxicity in primary neuron-microglia co-cultures. In vivo, intracerebroventricular administration of IL-34 ameliorated impairment of associative learning and reduced oA␤ 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 oA␤ neurotoxicity in AD.

Stroma-Derived Interleukin-34 Controls the Development and Maintenance of Langerhans Cells and the Maintenance of Microglia

“…IL-34 reporter expression revealed that within the brain, IL-34 is highly expressed predominantly in the cortex, the anterior olfactory nucleus, and the hippocampus (Figure 3A), whereas no or very low expression could be detected in the brain stem and cerebellum (data not shown). IL-34 was specifically expressed by neurons (Figure 3B) as previously suggested (Mizuno et al, 2011). In adult Il34 LacZ/LacZ mice, microglia were partially reduced, most pronounced in areas correlating with high IL-34 expression (Figures 3C–3E).…”

Focal Transplantation of Aberrant Glial Cells Carrying the SOD1^G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis

“…Accordingly, the pharmacological inhibition of CSF-1R decreases microglia reactivity and extends the life span of ALS mice [10,19]. Astrocytes are another major source of M-CSF and IL-34, both factors being potent agonists of the CSF-1R [20,21]. In support of this hypothesis, previous studies have shown that the intraperitoneal administration of M-CSF to ALS mice induced microglia proliferation, also exacerbating disease progression [22].…”

Neurons and astroglia govern microglial endotoxin tolerance through macrophage colony-stimulating factor receptor-mediated ERK1/2 signals

“…3d). Recent studies have shown that IL-34 is primarily produced by neurons, specifically directs the differentiation of myeloid cells in the developing CNS and determines the phenotype discrepancy in M-CSF-deficient and M-CSFR-deficient mice described above (Mizuno et al, 2011; Nandi et al, 2012; Wang et al, 2012). IL-34 deficiency mainly affects development but not the ability of microglia to produce inflammatory cytokines (Greter et al, 2012; Nakamichi et al, 2013; Wang and Colonna, 2014).…”