Alzheimer’s disease (AD), a devastating neurological condition with no known effective treatment, 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 beta-amyloid (Aβ) peptides in the brain causes synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Patients with mild cognitive impairment have elevated serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, I investigated the role of IL-33 in AD pathology in the APP/PS1 transgenic mouse model of AD. I found that IL...[ Read more ]

Alzheimer’s disease (AD), a devastating neurological condition with no known effective treatment, 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 beta-amyloid (Aβ) peptides in the brain causes synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Patients with mild cognitive impairment have elevated serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, I investigated the role of IL-33 in AD pathology in the APP/PS1 transgenic mouse model of AD. I found that IL-33 administration reversed synaptic plasticity impairment and memory deficits in APP/PS1 mice. In addition, IL-33 administration reduced soluble Aβ levels and amyloid plaque deposition by promoting the recruitment of microglia and their Aβ phagocytic activity, which are mediated by ST2/p38 signaling activation. Furthermore, IL-33 administration modulated the innate immune response by polarizing microglia/macrophages toward an anti-inflammatory phenotype and reducing the expressions of pro-inflammatory genes including IL-1β, IL-6, and NLRP3 in the cortices of APP/PS1 mice. My results also demonstrate that IL-33/ST2 signaling plays critical roles in hippocampal synaptic functions, as IL-33 administration increased the number of excitatory synapses in hippocampal neurons. Furthermore, IL-33 treatment increased the frequency of miniature excitatory postsynaptic currents and the field excitatory postsynaptic potentials of long-term potentiation in cultured hippocampal neurons and the mouse hippocampus, respectively, suggesting that IL-33 enhances spontaneous neurotransmission and synaptic strength. Thus, these results collectively suggest that IL-33 may have a therapeutic role in AD.