Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Teijido, Óscar

doi:10.3390/jpm8010003

Cited by 30 publications

(24 citation statements)

References 70 publications

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“…The expression or repression of all these genes and their products are regulated in a redundant and promiscuous fashion by the epigenetic machinery (DNA methylation/demethylation, histone/chromatin remodeling, and miRNA regulation), configuring the pharmacoepigenetic apparatus. The same enzyme/protein/transporter can process a multitude of drugs, and the same drug can be processed by a vast array of gene products in an orchestrated manner to operate as a security system against xenobiotic intruders [61][62][63][64][65][66][67].…”

Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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“…Evidence indicates that genomic, epigenomic, cerebrovascular, metabolic, and environmental factors might contribute to AD. [1] However, despite great progress in basic and clinical research of AD, its etiology remains largely unknown. Notably, the treatments for AD can only improve the symptoms to some extent without hampering the disease progression.…”

Section: Introductionmentioning

confidence: 99%

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

et al. 2018

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Alzheimer disease (AD) is a progressive neurodegenerative disease, the etiology of which remains largely unknown. Accumulating evidence indicates that elevated manganese (Mn) in brain exerts toxic effects on neurons and contributes to AD development. Thus, we aimed to explore the gene and pathway variations through analysis of high through-put data in this process.To screen the differentially expressed genes (DEGs) that may play critical roles in Mn-induced AD, public microarray data regarding Mn-treated neurocytes versus controls (GSE70845), and AD versus controls (GSE48350), were downloaded and the DEGs were screened out, respectively. The intersection of the DEGs of each datasets was obtained by using Venn analysis. Then, gene ontology (GO) function analysis and KEGG pathway analysis were carried out. For screening hub genes, protein-protein interaction network was constructed. At last, DEGs were analyzed in Connectivity Map (CMAP) for identification of small molecules that overcome Mn-induced neurotoxicity or AD development.The intersection of the DEGs obtained 140 upregulated and 267 downregulated genes. The top 5 items of biological processes of GO analysis were taxis, chemotaxis, cell-cell signaling, regulation of cellular physiological process, and response to wounding. The top 5 items of KEGG pathway analysis were cytokine-cytokine receptor interaction, apoptosis, oxidative phosphorylation, Toll-like receptor signaling pathway, and insulin signaling pathway. Afterwards, several hub genes such as INSR, VEGFA, PRKACB, DLG4, and BCL2 that might play key roles in Mn-induced AD were further screened out. Interestingly, tyrphostin AG-825, an inhibitor of tyrosine phosphorylation, was predicted to be a potential agent for overcoming Mn-induced neurotoxicity or AD development.The present study provided a novel insight into the molecular mechanisms of Mn-induced neurotoxicity or AD development and screened out several small molecular candidates that might be critical for Mn neurotoxicity prevention and Mn-induced AD treatment.

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“…We designed synthetic probes for NGS, targeting genes associated with dementia, SCZ, and several pharmacogenetic targets. The selection of genes was based on a literature search for published works reporting an effect of common variations or rare variants in SCZ, dementia or drug response to different antipsychotics or antidementia drugs 6,7,[26][27][28][29][30][31][32][33][34][35][36] ; a list of the captured genes is reported in Supplementary Table 1. Gene capture was performed using the Haloplex target enrichment system (Agilent Technologies, USA) with 1.51Mb with 40754 amplicons.…”

Section: Targeted Ngsmentioning

confidence: 99%

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

Martínez‐Magaña

Genis‐Mendoza

González-Covarrubias

et al. 2019

RIC

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Background: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer's type (DAT) or SCZ. Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.

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Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

Cited by 30 publications

References 70 publications

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

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