Transcriptome analysis of 3×Tg-AD mice exacerbated by HFD reveals novel molecular targets of Dendrobine protection

Abstract:

Background: The prevalence of Alzheimer's disease (AD) is increasing globally, and the progression of (AD) is now known to be exacerbated by high-fat diet (HFD). Dendrobine, an active alkaloid of Dendrobium nobile Lindl., is effective against AD models. This study aimed to examine the effects of Dendrobine on AD-HFD comorbidity and used RNA-Seq to explore the molecular targets. Methods: The AD-HFD comorbidity model was established by feeding 4-month-old 3×Tg-AD mice with HFD for 5 months. Dendrobine (1, 10 and 20 mg/kg, po) was administered staring 6-month-old for 3 months, and age-matched 3×Tg-AD mice fed normal diet were used as Controls. Behavioral tests were performed in 9-month-old mice, followed by histopathology. Hippocampal RNA was isolated and subjected to RNA-Seq and RT-qPCR analyses.  Results: Model mice exhibited more serious cognition deficits evidenced by Y maze, Novel object recognition, Open field, and Elevated plus maze. Nissl bodies in the hippocampus and cortex were decreased, while the expression of p-Tau (Thr231) increased. Dendrobine treatments ameliorated behavioral deficits and improved morphological lesions. RNA-Seq revealed distinct gene expression patterns among groups. Differentially expressed genes in Model mice were attenuated by Dendrobine and RT-qPCR verified selected genes. Ingenuity pathway analysis revealed metabolism disruption including downregulation of lipid metabolism and upregulation of “Mitochondrial Dysfunction”. AD-HFD increased upstream regulators related to oxidative stress and inflammation, while decreased molecules related to transcription factors for metabolism regulation. Dendrobine attenuated or reversed these molecular changes. Conclusions: AD-HFD comorbidity produced severer pathology than AD alone. Dendrobine is effective against behavioral, pathological, and transcriptomic changes in Model mice, probably through targeting aberrant lipid metabolism, inflammation, and neurodegeneration in AD-HFD comorbidity mice.