mRNA profiling reveals the potential mechanism of TIPE2 in attenuating cognitive deficits in APP/PS1 mice

Abstract

Chronic brain neuritis is important for the pathogenesis and progression of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-α (TNFα)-inducible protein 8-like 2 (TIPE2), a novel immunoregulatory protein, reverses cognitive dysfunction in APP/PS1 mice. However, the mRNA profile changes in TIPE2 overexpression APP/PS1 mice and the molecular mechanism of cognitive attenuation remain unknown. In this study, after the Y-maze testing the spatial learning of the APP/PS1 mice and the TIPE2 overexpression APP/PS1 mice, high-throughput sequencing was performed on hippocampus tissues for analysis of mRNA profiles. A total of 183 differentially expressed genes (DEGs) were detected, of which 36 were down-regulated and 147 were up-regulated. Then, the mRNA profiles of the APP/PS1 mice and the wild-type mice were analyzed. A total of 196 DEGs were detected, of which 105 were down-regulated and 91 were up-regulated in the APP/PS1 mice. A comprehensive comparison of the mouse mRNAs showed that 20 genes were differentially expressed in both groups, among which, 19 genes showed an altered expression in the APP/PS1 mice, and the expression was recovered in TIPE2 overexpression APP/PS1 mice. We selected seven genes from these 19 genes, including Ttr, Lepr, Angptl2, Otx2, Clic6, Clo4a3 and Wfdc, for high-throughput sequencing. The results showed that, compared to the wild-type mice, these 7 genes were significantly down-regulated in the hippocampus of APP/PS1 mice. The expressions of a selected list of DEGs between APP/PS1 mice and APP/PS1 + OE mice were validated by quantitative real-time RT-PCR (qRT-PCR), and the results were consistent with the sequencing analysis. Taken together, increased adeno-associated virus (AAV)-mediated TIPE2 overexpression in the hippocampus of APP/PS1 mice reversed cognitive dysfunction. Transcriptional sequencing and bioinformatics analysis indicate that the attenuation of cognitive deficits was attributed to the recovery of certain genes.

Keywords: Alzheimer’s disease; Hippocampus; TIPE2; mRNA Sequencing.