THESIS
2018
xiv, 154 pages : illustrations (some color) ; 30 cm
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease and the leading cause of dementia.
Abnormal production and accumulation of amyloid-beta (Aβ) peptides are critical in the
pathogenesis of AD. Increasing evidence indicates that microglia, which are the resident myeloid
cells in the central nervous system, exert important effects on Aβ metabolism. Interleukin (IL)-33
ameliorates AD-like pathology by modulating microglial function in APP/PS1 mice, an AD
transgenic mouse model. The present study showed that in APP/PS1 mice, IL-33 expression in the
cortex is downregulated, whereas the microglial expression of its receptor, ST2, is upregulated. In
addition, the ST2
+ microglia subpopulation has higher Aβ uptake capacity, which is further
promoted by IL-33 administration. These re...[
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Alzheimer’s disease (AD) is a neurodegenerative disease and the leading cause of dementia.
Abnormal production and accumulation of amyloid-beta (Aβ) peptides are critical in the
pathogenesis of AD. Increasing evidence indicates that microglia, which are the resident myeloid
cells in the central nervous system, exert important effects on Aβ metabolism. Interleukin (IL)-33
ameliorates AD-like pathology by modulating microglial function in APP/PS1 mice, an AD
transgenic mouse model. The present study showed that in APP/PS1 mice, IL-33 expression in the
cortex is downregulated, whereas the microglial expression of its receptor, ST2, is upregulated. In
addition, the ST2
+ microglia subpopulation has higher Aβ uptake capacity, which is further
promoted by IL-33 administration. These results indicate that IL-33/ST2 signaling is regulated
during AD pathogenesis and promotes microglial Aβ uptake. RNA sequencing revealed that IL-33
alters the transcriptome profile of microglia in APP/PS1 mice, which is associated with
inflammatory response and phagocytosis. Further analysis suggested that ST2
+ microglia have
higher CD14 and MHC II expression, which is correlated with microglial Aβ phagocytosis. Thus,
the results collectively demonstrate how IL-33/ST2 signaling modulates microglia towards a
beneficial phenotype characterized by higher Aβ phagocytic ability. Therefore, IL-33 could be
developed as a therapeutic strategy for the treatment of AD.
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