Objective To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior, glia activation and pro-inflammatory cycokines, and Tau phosphorylation of a new Alzheimer's disease (AD) mouse model carrying a PSEN1 p.G378E mutation. Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation, and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice (PSEN1G378E/WT; Tyrobp+/?) and the homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp?/?). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed, the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and ELISA to measure the levels of pro-inflammatory cytokines. Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in PSEN1G378E mutation mouse model prevented the deterioration of learning behavior, decreased the numbers of microglia and astrocytes, and the levels of interleukin-6, interleukin-1β and tumor necrosis factor-α in the hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/ Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp?/? mice) compared with PSEN1G378E/G378E mice (all P < 0.05). Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However, the relationship between neuroinflammation processes involving microglia and astrocyte activation, and release of pro-inflammatory cytokines, and p-Tau pathology needs further study.

Ran Li;Zhanyun Lv;Yanxin Li;Wei Li;Yanlei Hao

School of Basic Medical Sciences,Shandong University,Jinan 250012,China;Zhejiang University Medical Center,Hangzhou 311121,China;Department of Neurology,Pingdu People's Hospital,Qingdao,Shandong 266799,China;Department of Neurology,Affliated Hospital of Jining Medical College,Jining,Shandong 272007,China

中国医学科学杂志（英文版）

[1]Ran Li;Zhanyun Lv;Yanxin Li;Wei Li;Yanlei Hao-.Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer's Disease Mouse Model Carrying a PSEN1 p.G378E Mutation)[J].中国医学科学杂志（英文版）,2022(04):320-330

G378E,TYRO,cycokines,PSEN1G378E,Tyrobp+,Tau5,PHF1,pT181,pT231

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