Intracerebral microinjection of interleukin-4/interleukin-13 reduces β-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice

Kikuchi, Kôichi; Suenobu, Michita; Yoshida, Akira; Koga, Kiyohiro; Hyodo, Atsushi; Ohtsuka, Hideyuki; Kuniyasu, Akihiko; Tamamaki, Nobuaki; Sugimoto, Yukihiko; Nakayama, Hitoshi

doi:10.1016/j.neuroscience.2012.01.049

Cited by 101 publications

(80 citation statements)

References 57 publications

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“…Support for this theory is provided by findings of increased expression of M1 markers such as CD40 [56], and major histocompatibility complex Class II (MHC-II) [77,78], in the AD brain. Additional support comes from in vitro studies showing M2 polarization and stimulated phagocytosis of A␤ in rat microglia that were stimulated with IL-4 [79], and from a study in which Th2 cytokines were found to reduce A␤ accumulation and improve cognition in a transgenic mouse model resembling AD [80].…”

Section: Discussionmentioning

confidence: 99%

Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-β42 by Human Microglia and Decrease Inflammatory Markers

Hjorth

Zhu

Toro

et al. 2013

JAD

200

154

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Abstract. The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-␤ (A␤), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of A␤ 42 . Phagocytosis of A␤ 42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of A␤ 42 . Phagocytosis of A␤ 42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-␣ were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of A␤ 42 , increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.

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Section: Discussionmentioning

confidence: 99%

Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-β42 by Human Microglia and Decrease Inflammatory Markers

Hjorth

Zhu

Toro

et al. 2013

JAD

200

154

View full text Add to dashboard Cite

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“…Like macrophage, microglia polarize to M1 state by stimulation with LPS plus IFNg and produce reactive oxygen species (ROS) and proinflammatory factors, such as TNF-a, IL-1b, IL-6 [23]. In contrast, several studies showed that IL-4 and IL-13 can up-regulate the expressions of Arg-1, Ym1, and CD36 in activated microglia and decrease the level of TNF-a in the CNS of mice [24]. So, IL-4 and IL-13 can induce microglia to polarize to M2 state, which express M2 markers, anti-inflammatory and neurotrophic factors, such as IL-10, BDNF and GDNF [23,25].…”

Section: Discussionmentioning

confidence: 99%

Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling

Jia

Liu

et al. 2015

Biochemical and Biophysical Research Communications

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“…5A), suggesting that functional IL-4 signaling may be impaired in hippocampus of 8.5-month-old A␤PP23 mice, and that the A␤PP23 mice produce more IL-4 to compensate for the functional defect. We previously showed that intracerebral microinjection of IL-4/IL-13 reduced A␤ levels and improved cognitive deficits in A␤PP23 mice, possibly by activating IL-4R␣-positive M2-like microglia [63]. Th2-biased immune responses induced by retinoids may serve to restore IL-4 signaling [23].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Kawahara

Suenobu

Ohtsuka

et al. 2014

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)␣,␤ agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-␤ protein precursor 23 (A␤PP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in A␤PP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A␤ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A␤ peptide in 8.5-month-old A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to A␤ clearance in Am80/HX630-treated A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric A␤ peptides by restoring impaired IL-4 signaling in A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

show abstract

Intracerebral microinjection of interleukin-4/interleukin-13 reduces β-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice

Cited by 101 publications

References 57 publications

Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-β42 by Human Microglia and Decrease Inflammatory Markers

Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-β42 by Human Microglia and Decrease Inflammatory Markers

Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

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