IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline.
Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Amy K Y
AK
Fu
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Kwok-Wang
KW
Hung
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Michael Y F
MY
Yuen
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Xiaopu
X
Zhou
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Deejay S Y
DS
Mak
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Ivy C W
IC
Chan
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Tom H
TH
Cheung
Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China;
Baorong
B
Zhang
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
Wing-Yu
WY
Fu
Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom; School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215006, China foo.liew@glasgow.ac.uk boip@ust.hk.
Foo Y
FY
Liew
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; foo.liew@glasgow.ac.uk boip@ust.hk.
Nancy Y
NY
Ip
D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000067596:Interleukin-33 / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000008:administration & dosage; D016896:Treatment Outcome
D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D018696:Neuroprotective Agents
innate immunity; microglia; neuroninflammation; synaptic plasticity; β-amyloid