Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice

• DOI: 10.1007/s11481-019-09861-2
• Publication Date: 2019-07-08T06:02:45Z
• Authors: Yongzhen Miao; Naidong Wang; Wenjin Shao; Zihan Xu; Zhihong Yang; Lei Wang; Chuanxia Ju; Ruoyu Zhang; Fang Zhang
• Keywords: Memory Disorders; 0303 health sciences; Genetic Vectors; Intracellular Signaling Peptides and Proteins; Gene Expression Regulation, Developmental; Fear; Genetic Therapy; Adaptive Immunity; Dependovirus; Hippocampus; Immunity, Innate; Injections; Mice, Inbred C57BL; Amyloid beta-Protein Precursor; Disease Models, Animal; Mice; 03 medical and health sciences; Alzheimer Disease; Animals; Cytokines; Cognition Disorders; Maze Learning

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. Graphical Abstract .