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The histamine H4 receptor antagonist has been shown to inhibit microgliosis in vivo. Reducing microgliosis helps to decrease the amount of pro-inflammatory cytokines and protect the adjacent neurons. Also, reducing microglial M1 phenotype activation and increasing the microglial M2 phenotype could facilitate the microglial phagocytosis of misfolding proteins, including fibrillar forms of Aβ (amyloid beta). Our preliminary results demonstrated that the histamine H4 receptor antagonist can improve the long- and short-term spatial memory deficits in three types of mice with Alzheimer’s disease (AD). We believe that the histamine H4 receptor antagonist has a potential beneficial effect for treating AD.