THESIS
2018
xiv, 136 pages : illustrations (some color) ; 30 cm
Abstract
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...[
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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.
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