Alzheimer’s disease (AD) is a fatal neurodegenerative disease that underlies majority of elderly patients suffering from dementia. The disease is characterized by two pathological hallmarks: excessive deposition of extracellular amyloid beta peptide (Aβ) and abnormal aggregation of intracellular tau protein. Many studies suggest that prolonged neuroinflammation triggered by Aβ plaques critically contributes to AD development. As brain resident macrophage called microglia potentiates neuroinflammation, many recent studies highlight the roles of microglia in AD. In fact, a piling body of works demonstrates that modulating microglial phenotype can reduce AD severity in animal models. IL-33 is one of cytokine alarmins that can activate microglia and modulate their cellular functions. Inject...[ Read more ]

Alzheimer’s disease (AD) is a fatal neurodegenerative disease that underlies majority of elderly patients suffering from dementia. The disease is characterized by two pathological hallmarks: excessive deposition of extracellular amyloid beta peptide (Aβ) and abnormal aggregation of intracellular tau protein. Many studies suggest that prolonged neuroinflammation triggered by Aβ plaques critically contributes to AD development. As brain resident macrophage called microglia potentiates neuroinflammation, many recent studies highlight the roles of microglia in AD. In fact, a piling body of works demonstrates that modulating microglial phenotype can reduce AD severity in animal models. IL-33 is one of cytokine alarmins that can activate microglia and modulate their cellular functions. Injecting IL-33 was shown to ameliorate AD-like pathology in APP/PS1 transgenic mice which is a mouse model of AD. This study showed that microglial expression of ST2, which is the receptor of IL-33, is upregulated in APP/PS1 transgenic mice. Moreover, in vivo labelling of Aβ revealed that ST2⁺ microglia have enhanced phagocytic capability towards Aβ. Bulk RNA-seq analysis of the ST2⁺ microglia identified many enriched biological pathways and genes. This suggested that ST2⁺ microglia have altered immune and metabolic functions. CRISPRa screening was also attempted to reveal transcription factors that can drive ST2 expression in microglia. This together heightened the significance of microglial IL-33/ST2 signaling pathway in etiopathology of AD.