Transcriptome analysis of fasudil treatment in the APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is the most common cause of progressive dementia. In the present study, we showed hippocampal tissue transcriptome analysis in APPswe/PSEN1dE9 (APP/PS1, AD model) mice treated with fasudil (ADF) and compared with AD mice treated with saline (ADNS) and wild type mice (WT). The competing endogenous RNA (ceRNA) network was constructed and validated the differential expression of mRNA, lncRNA, miRNA, and circRNA. Our study showed differentially expressed mRNAs (DEMs) between WT and ADNS, while enriched in cell growth and death and nervous system pathways. DEMs between ADNS-ADF were enriched in the nervous system, glycosaminoglycan biosynthesis-keratan sulfate (KS) and Quorum sensing pathways. We validated four genes with RT-PCR, whereas enrichment of Acyl-CoA Synthetase Long Chain Family Member 4 (Acsl4, ENSMUST00000112903) in Quorum sensing pathways, and BTG anti-proliferation factor 1 (Btg1, ENSMUST00000038377) in RNA degradation pathways were conducted. Expression of these two genes were higher in ADNS, but were significantly reduced in ADF. Histone H4 transcription factor (Hinfp, ENSMUST00000216508) orchestrate G1/S transition of mitotic cell cycle and co-expressed with mmu-miR-26a-2-3p-mediated ceRNA and mmu-miR-3065-5p-mediated ceRNA; Wnt family member 4 (Wnt4, ENSMUST00000045747) was enriched in mTOR, Hippo and Wnt signaling pathway. Expression of these two genes were significantly lower in ADNS, and fasudil treatment reverse it. The present studies demonstrated four genes: Acsl4, Btg1, Hinfp, Wnt4 could be potential biomarkers of AD and the targets of fasudil treatment. These results will pave a novel direction for future clinic studies for AD and fasudil treatment.

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer’s disease mice

“…Although transcriptome studies have previously been carried out in APP/PS1 AD mice, these studies exhibit some limitations in design that affect their informative value. The latter is mainly related to the combined analysis of sexes [ 37 , 38 , 81 ], the selective analysis of males only [ 41 – 43 ], an unspecified sex distribution [ 39 , 82 ], analysis of only one brain region [ 37 , 39 , 40 , 43 , 81 ], investigation of no distinct brain region (e.g., cortex in total [ 41 , 42 ] or the analysis of entire brain probes [ 38 ] ( S15 Table in S1 File ). Based on our previous findings on distinct electrophysiological alterations in the APP/PS1 AD model related to sex, age and brain region [ 13 , 14 ], we performed transcriptome studies in the RS cortex and hippocampus of both sexes in WT controls and APP/PS1 mice.…”

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

“…To date, fasudil, as well as its analogues, are the most investigated ROCK inhibitors. Many studies have shown that the compound improves memory deficits, significantly reduces Aβ and p-tau protein levels, restores cognitive function, reduces oxidative stress, and decreases neuronal apoptosis in the hippocampus [ 111 , 112 , 113 , 114 ].…”

An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases

“…AA consumption is elevated in patients with AD, indicating an excess of AA in the human diet could constitute a risk factor for AD ( Rapoport, 2008 ). In APP/PS1 mice (APPswe/PSEN1dE9 transgenic mice model of AD), transcriptome analysis identified the enriched ACSL4 ( Yan et al, 2022 ), which can be inhibited by tetrahydroxy stilbene glycoside (TSG) ( Gao et al, 2021 ). Besides, N2L, a novel lipoic acid-niacin dimer regulating lipid metabolism with multifunction, was also proved to exert neuroprotective effects by blocking the increase of ACSL4 protein expression ( Peng et al, 2021 ).…”