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Guanosine monophosphate reductase 1 is a potential therapeutic target for Alzheimer′s disease

By Hongde Liu, Kun Luo

Posted 08 Nov 2017
bioRxiv DOI: 10.1101/215947 (published DOI: 10.1038/s41598-018-21256-6)

Alzheimer′s disease (AD) is a severe neurodegenerative disorder. Identification of differentially expressed genes in AD would help to find biomarker and therapeutic target. Here, we carried out an analysis to identify the age-independent and AD-specific genes. We found that genes MET, WIF1 and NPTX2 are down regulated in AD. WIF1 and MET are in signaling of WNT and MET, regulating the activity of GSK3B, thus in AD. Importantly, we found gene GMPR shows a gradual increase in AD progress. A logistic model based on GMPR exhibits a good capacity in classifying AD cases. GMPR′s product GMPR1 links with AMPK and adenosine receptor pathways, thus associating phosphorylation of Tau in AD. This allows GMPR1 to be a therapeutic target. Therefore, we screened five possible inhibitors to GMPR1 by docking GMPR1 with 1174 approved drugs. Among them, lumacaftor is ideal due to its high affinity and light molecular weight. We then tested the effect of lumacaftor on AD model mice. After twenty days of oral administration, Amyloid-beta accumulation is slowed down and phosphorylation of Tau is almost eliminated in the treated mice, showing a satisfying effect. In conclusion, the elevated expression level of GMPR tightly associates with AD progress and leads to AD phenotype probably through AMPK and adenosine receptor pathways; and one of therapeutic strategies is to inhibit GMPR′s product with lumacaftor.

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