Guanosine monophosphate reductase 1 is a potential therapeutic target for Alzheimer’s disease
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Abstract
Abstract 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 GSK3β, 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, β-Amyloid 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. Significance Statement We found the elevated expression level of GMPR tightly associates with AD progress and leads to AD phenotype probably through AMPK and adenosine receptor pathways; and the therapeutic strategy targeting GMPR1 with lumacaftor shows a satisfying result.
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Clinical literature shows low levels of MET protein in the brains of AD patients and the MET gene as the most downregulated by transcriptome analysis.
“These findings are in keeping with clinical literature showing low levels of MET protein in the brains of AD patients and the MET gene as the most downregulated by transcriptome analysis [122,123].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [123]
The Results section on age-independent differentially expressed genes reports lower MET gene expression in AD brain samples. It lists several downregulated genes but does not identify MET as the most downregulated, and it does not report MET protein levels in patients’ brains. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLong-term infection depressed the 26S proteasome ubiquitination system by downregulation of Psmd8 and Psmc6.
“The long term infection also depressed the 26S proteasome ubiquitination system by downregulation of Psmd883 and Psmc684 leading to persistence of stress-induced protein aggregates.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [83]
The Results section on age-independent differentially expressed genes identifies PSMD8 as a 26S proteasome subunit, but does not report that infection downregulates it. Searches for long-term infection, PSMC6, and proteasome suppression found no passage addressing the claimed effect or its link to persistent protein aggregates. No page number is available in our copy. (LLM, conf=0.75)
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References 40 · Cited by 42
- Authors
- Liu, H., Luo, K., & Luo, D.
- Affiliations
- State Key Laboratory of Digital Medical Engineering (CN)
- Xinjiang Medical University (CN)
- First Affiliated Hospital of Xinjiang Medical University (CN)
- Corresponding author
- Liu, Hongde
- Luo, Kun
- ORCID
- Venue
- Scientific Reports
- Published
- 2018-02-09
- Volume
- 8
- Issue
- 1
- Pages
- 2759-2759
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5807363
- OpenAlex
- W2949561238
- Cited by
- 42
- References
- 40
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 1
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (31371339, BE2016002-3, No. 31371339, No. 81660471, 81660471)
- Government of Jiangsu Province (BE2016002-3, BE2016002)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, therapeutic target, lumacaftor, drug repurposing, C-MET signaling, WIF1, NPTX2, GSK3β, AMPK signaling, adenosine receptors, tau phosphorylation, amyloid-beta deposition
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Pentraxins, Alzheimer Disease, Aminopyridines, Animals, C-Reactive Protein, Disease Models, Animal, Enzyme Inhibitors, Nerve Tissue Proteins, Phosphorylation, Repressor Proteins, Amyloid beta-Peptides, tau Proteins, Proto-Oncogene Proteins c-met, Databases, Genetic, Adaptor Proteins, Signal Transducing, GMP Reductase, Mice, Benzodioxoles, Molecular Targeted Therapy, Wnt Signaling Pathway
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