The common genes involved in the pathogenesis of Alzheimer's disease and type 2 diabetes and their implication for drug repositioning

Yuan, Xin; Wang, Hao; Zhang, Fengyu; Zhang, Meidi; Wang, Qiuchen; Wang, Ju

doi:10.1016/j.neuropharm.2022.109327

Cited by 16 publications

(16 citation statements)

References 73 publications

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“…Disturbed insulin signaling in endothelial cells and insulin resistance can promote inflammation and dyslipidemia. INS, VEGFA, and TNF may interact to promote the formation of plaques and the development of atherosclerosis [34,35] . KEGG analysis revealed that the targets are mainly concentrated in the HIF‐1 signaling pathway, viscosity, atherosclerosis, and adipocytokine signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach

Wang

Zhou

et al. 2023

Chemistry & Biodiversity

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The therapeutic effect of apigenin (APG) on hyperlipidemia was investigated using network pharmacology combined with molecular docking strategy, and the potential targets of APG in the treatment of hyperlipidemia were explored. Genetic Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis of common targets were performed. Then, molecular docking was used to predict the binding mode of APG to the target. Finally, Sprague Dawley rats were used to establish a hyperlipidemia model. The expression levels of insulin (INS) and vascular endothelial growth factor A (VEGFA) mRNA in each group were detected by quantitative reverse transcription-polymerase chain reaction. Network pharmacological studies revealed that the role of APG in the treatment of hyperlipidemia was through the regulation of INS, VEGFA, tumor necrosis factor, epidermal growth factor receptor, matrix metalloprotein 9, and other targets, as well as through the regulation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway, fluid shear stress, and atherosclerosis signaling pathways, vascular permeability; APG also participated in the regulation of glucose metabolism and lipid metabolism, and acted on vascular endothelial cells, and regulated vascular tone. Molecular docking showed that APG binds to the target with good efficiency. Experiments showed that after APG treatment, the expression levels of INS and VEGFA mRNA in the model group were significantly decreased (p < 0.01). In conclusion, APG has multiple targets and affects pathways involved in the treatment of hyperlipidemia by regulating the HIF-1 signaling pathway, fluid shear stress, and the atherosclerosis pathway.

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach

Wang

Zhou

et al. 2023

Chemistry & Biodiversity

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“…In addition, the pathological processing of Tau and Aβ, such as other neuropathological events, could be triggered by some genes involved in metabolic disorders ( Figure 2 and Table 1 ); mainly lipid/atherosclerosis pathways and insulin resistance [ 57 ]. In this context, the solute carrier family 10 member 2 ( SLC10A2 ) plays an important role in the regulation of cholesterol metabolism, and it has been shown that cholesterol accumulation in neurons leads to neuronal death, memory impairment, and increased Aβ generation [ 58 , 59 ].…”

Section: Unraveling the Genetics Of Alzheimer’s Disease: What Is New?mentioning

confidence: 99%

“…In this context, the solute carrier family 10 member 2 ( SLC10A2 ) plays an important role in the regulation of cholesterol metabolism, and it has been shown that cholesterol accumulation in neurons leads to neuronal death, memory impairment, and increased Aβ generation [ 58 , 59 ]. Since AD could be considered a metabolic disease mediated in part by insulin resistance [ 57 ], it is postulated that the zinc finger CW-type PWWP domain protein 1 (ZCWPW1 ), a protein involved in the positive regulation of the DNA metabolic process, could decrease the risk of LOAD by suppressing insulin resistance [ 60 ]. Furthermore, genes involved in the AMP-activated protein kinase (AMPK) pathway have also been associated with the risk of AD by regulation of energy balance and glucose and lipid metabolism [ 61 ], autophagy dysfunctions leading to Aβ and Tau pathology [ 57 ], and alteration of the synaptic plasticity of hippocampal neurons [ 62 ].…”

Section: Unraveling the Genetics Of Alzheimer’s Disease: What Is New?mentioning

confidence: 99%

“…Since AD could be considered a metabolic disease mediated in part by insulin resistance [ 57 ], it is postulated that the zinc finger CW-type PWWP domain protein 1 (ZCWPW1 ), a protein involved in the positive regulation of the DNA metabolic process, could decrease the risk of LOAD by suppressing insulin resistance [ 60 ]. Furthermore, genes involved in the AMP-activated protein kinase (AMPK) pathway have also been associated with the risk of AD by regulation of energy balance and glucose and lipid metabolism [ 61 ], autophagy dysfunctions leading to Aβ and Tau pathology [ 57 ], and alteration of the synaptic plasticity of hippocampal neurons [ 62 ]. Correspondingly, methylenetetrahydrofolate reductase (MTHFR ), a rate-limiting enzyme in the methyl cycle, can be linked, as high levels of homocysteine have been found in AD patients.…”

Section: Unraveling the Genetics Of Alzheimer’s Disease: What Is New?mentioning

confidence: 99%

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Alzheimer’s Disease: An Updated Overview of Its Genetics

Andrade-Guerrero

Santiago-Balmaseda

Jeronimo-Aguilar

et al. 2023

IJMS

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Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1–5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.

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“…Recently, genetic polymorphisms in genes that have been implicated in AD, a primary neurodegenerative disease and the most common cause of dementia worldwide [ 85 ], include, among others, ABCA7 [ 86 ], PICALM [ 87 ], CLU [ 88 ], SLC24A4/RIN3 [ 89 ], ECHDC3 [ 90 ], MTHFR [ 91 ], as well as in insulin signaling such as INSR [ 92 ]. MTHFR mutations are associated with homocysteinemia, and increased homocysteine blood levels are considered to be an independent risk factor of cerebrovascular incidents.…”

Section: Introductionmentioning

confidence: 99%

Controlling the Impact of Helicobacter pylori-Related Hyperhomocysteinemia on Neurodegeneration

et al. 2023

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Helicobacter pylori infection consists a high global burden affecting more than 50% of the world’s population. It is implicated, beyond substantiated local gastric pathologies, i.e., peptic ulcers and gastric cancer, in the pathophysiology of several neurodegenerative disorders, mainly by inducing hyperhomocysteinemia-related brain cortical thinning (BCT). BCT has been advocated as a possible biomarker associated with neurodegenerative central nervous system disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and/or glaucoma, termed as “ocular Alzheimer’s disease”. According to the infection hypothesis in relation to neurodegeneration, Helicobacter pylori as non-commensal gut microbiome has been advocated as trigger and/or mediator of neurodegenerative diseases, such as the development of Alzheimer’s disease. Among others, Helicobacter pylori-related inflammatory mediators, defensins, autophagy, vitamin D, dietary factors, role of probiotics, and some pathogenetic considerations including relevant involved genes are discussed within this opinion article. In conclusion, by controlling the impact of Helicobacter pylori-related hyperhomocysteinemia on neurodegenerative disorders might offer benefits, and additional research is warranted to clarify this crucial topic currently representing a major worldwide burden.

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The common genes involved in the pathogenesis of Alzheimer's disease and type 2 diabetes and their implication for drug repositioning

Cited by 16 publications

References 73 publications

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach

Alzheimer’s Disease: An Updated Overview of Its Genetics

Controlling the Impact of Helicobacter pylori-Related Hyperhomocysteinemia on Neurodegeneration

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