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IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide_1–42 by Rat Primary Type 2 Microglia¹

Eisuke Shimizu^*, Kohichi Kawahara^*, Makoto Kajizono^*, Makoto Sawada and Hitoshi Nakayama^2,*

^* Department of Molecular Cell Function, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; and Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ_1–42 (o-Aβ_1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of ¹²⁵I-labeled o-Aβ_1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ_1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ_1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ_1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ_1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research of Priority Area "Glia-Neuron Network" 16047224 and 18053019 (to H.N.) and for Scientific Research Grants 15390029 and 19390031 (to H.N.) and 17790067 (to K.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Hitoshi Nakayama, Department of Molecular Cell Function, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. E-mail address: jin{at}gpo.kumamoto-u.ac.jp

³ Abbreviations used in this paper: AD, Alzheimer’s disease; Aβ, β-amyloid; BBB, blood-brain barrier; CHO, Chinese hamster ovary; IDE, insulin-degrading enzyme; MG, microglia; NEP, neprilysin; o-Aβ_1–42, oligomeric Aβ_1–42; RAGE, receptor for advanced glycation end product; SRA, scavenger receptor class AI/AII; SR-BI, scavenger receptor class B type I.