Open Access
Epigenetics of brain aging
(Academic Press, 2018) Cacabelos, Ramón; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
The complexity of human aging and longevity results from a combination of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation, chromatin structure, and RNA interference, regulate gene expression and control the main metabolic pathways throughout life. This strict epigenetic management becomes progressively defective with age, which increases the risk for the onset of age-related pathologies. This chapter reviews the main alterations of the epigenetic machinery throughout life, with special focus on those affecting the aging brain, as well as the epigenetic control of life span by regulating telomere length and mitochondrial function, with special emphasis on the epigenetic interplay between nuclear and mitochondrial DNA. The last section summarizes the main epigenetic aberrations involving the most prevalent form of pathologic brain deterioration in elderly individuals, Alzheimer's disease, and novel potential epigenetic-based treatments.
Open Access
Epigenetic drug discovery for alzheimer's disease
(Academic Press, 2018) Cacabelos, Ramón; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease (AD) is the most important neurodegenerative disorder in Western countries. Pathological phenotypes of neurodegeneration result from a combination of genomic, epigenomic, metabolic, and environmental factors, which hinders their treatment. Current FDA-approved conventional drugs are purely symptomatic but incapable to halt or, at least, delay the progression of the disease. The epigenetic approach allows the identification of key pathological targets in complex disorders that cannot be explained by conventional genetics. Many of these epigenetic targets may be detected in early asymptomatic stages of the disease. Furthermore, the reversibility and potential restoring of epigenetic aberrations, unlike genetic mutations, sited epigenetic-based therapy as a promising tool to treat those complex disorders. This chapter reviews the main potential epigenetic-based compounds that have been used for preclinical studies during the last decade and those currently submitted to clinical trials for the treatment of AD.
Open Access
Pharmacogenetic considerations in the treatment of Alzheimer's disease
(Taylor & Francis, 2016) Cacabelos, Ramón; Torrellas, Clara; Teijido Hermida, Óscar; Carril, Juan Carlos ; Ciencias de la Salud; Osasun Zientziak
The practical pharmacogenetics of Alzheimer’s disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug–drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.
Open Access
Pharmacoepigenomic interventions as novel potential treatments for Alzheimer's and Parkinson's diseases
(MDPI, 2018) Teijido Hermida, Óscar; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.
Open Access
Pharmacogenetics of vascular risk factors in Alzheimer's disease
(MDPI, 2018-01-03) Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.
Open Access
Can cloud-based tools accelerate Alzheimer's disease drug discovery?
(Taylor & Francis, 2016) Cacabelos, Ramón; Teijido Hermida, Óscar; Carril, Juan Carlos; Ciencias de la Salud; Osasun Zientziak
Open Access
Pharmacogenomics of Alzheimer's disease: genetic determinants of phenotypic variation and therapeutic outcome
(SciTech Central, 2016-11-16) Cacabelos, Ramón; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Goldgaber, Dmitry; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Conventional anti-dementia drugs are not cost-effective, and pharmacological breakthroughs have not been achieved for the past 10 years. Major determinants of therapeutic outcome in Alzheimer's disease (AD) include age- and sex-related factors, pathogenic phenotype, concomitant disorders, treatment modality and polypharmacy, and pharmacogenetics. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety. Pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes represent the major genetic determinants of response to treatment in AD. In pharmacogenetic studies, APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments. Patients harboring a large (L) number of poly T repeats in intrón 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders whereas patients with short (S) TOMM40 poly T variants (S/S genotype), and to a lesser extent S/VL and VL/VL carriers, in haplotypes with APOE-3 are the best responders to treatment. Only 25% of the Caucasian population are extensive metabolizers for trigenic haplotypes integrating CYP2D6- CYP2C19-CYP2C9 variants. Patients harboring CYP-related por (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG- AG-CC) exhibit the lowest cholesterol levels and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Epigenetic aberrations (DNA methylation, histone modifications, miRNA dysregulation) in genes configuring the pharmacoepigenetic cascade also influence the response/resistance to drugs. Consequently, novel strategies in drug development, either preventive or therapeutic, for AD should take into consideration these pharmacogenetic determinants for treatment optimization.
Open Access
Epigenomics and proteomics of brain disorders
(SciTech Central, 2017-11-30) Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Epigenomic mechanisms (DNA methylation, chromatin remodeling/histone modifications, miRNA regulation) are involved in the transcriptional and post-translational regulation of genes in physiological and pathological conditions leading to potentially reversible phenotypes. Mutations in the genes encoding elements of the epigenetic machinery cause epigenetic Mendelian disorders. Epigenetic aberrations contribute to the pathogenesis of neurodevelopmental, imprinting, neuropsychiatric, and age-related neurodegenerative disorders. Some brain disorders exhibit proteoepigenomic changes resulting from primary genomic traits and/or secondary epigenetic events which induce pathogenic (structural, functional, conformational) changes in key proteins. Proteomic biomarkers and epigenomic signatures may help in the prediction, early diagnosis, and prognosis of CNS disorders. Epigenetic drug discovery, application of pharmacoepigenomic procedures for personalized therapeutics, novel approaches to decode and resolve drug resistance, and targeting miRNAs in prevention and treatment of brain disorders are promising areas of future development.
Open Access
Population-based study of risk polymorphisms associated with vascular disorders and dementia
(Bentham Science Publishers, 2017) Teijido Hermida, Óscar; Carril, Juan Carlos ; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Introduction: Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies. Aims: The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome. Material & Method: We performed a cross-sectional study on 4415 individuals from a widespread regional distribution in Spain (48.15% males and 51.85% females), with mental, neurodegenerative, cerebrovascular, and metabolic disorders. We evaluated polymorphisms in 20 genes involved in obesity, vascular and cardiovascular risk, and dementia in our population and compared it with representative Spanish and European populations. Risk polymorphisms in ACE, AGT(235), IL6(573), PSEN1, and APOE (specially the APOE-ε4 allele) are representative of our population as compared to the reference data of Spanish and European individuals. Conclusion: The significantly higher distribution of risk polymorphisms in PSEN1 and APOE-ε4 is characteristic of a representative number of patients with Alzheimer’s disease; whereas polymorphisms in ACE, AGT(235), and IL6(573), are most probably related with the high number of patients with metabolic syndrome or cerebrovascular damage.
Open Access
Biochemistry, cytogenetics and DMD gene mutations in south indian patients with Duchenne muscular dystrophy
(Kamla-Raj Enterprises, 2017) Meyyazhagan, Arun; Raman, N. M.; Easwaran, M.; Balasubramanian, B.; Alagamuthu, K.; Kuchi Bhotla, H.; Shanmugam, S.; Inbaraj, K.; Ramesh Kumar, M.; Kumar, P.; Thangamani, L.; Piramanayagam, S.; Anand, V.; Mohd, Y.; Park, S.; Teijido Hermida, Óscar; Carril, Juan Carlos; Cacabelos, Pablo; Keshavarao, S.; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Thirty children aged 3-10 years with clinically confirmed or suspected Duchenne Muscular Dystrophy (DMD) were analyzed for chromosomal aberrations using cytological preparations, biochemical changes using enzyme kit protocol, and deletions in the 26 exons of the DMD gene by targeting the mutations at the proximal and distal ‘hot spot’ regions of the dystrophin gene in South Indian patients with DMD. The frequency of chromosomal aberrations (both chromosomal and chromatid-type) and serum enzyme levels were significantly elevated in DMD subjects as compared to controls. Multiplex PCR assays revealed 27 patients having deletions in the DMD gene located at the distal ‘hot spot’ region. This study suggests that disease progression is directly associated with higher incidence of the deletions at the distal ‘hot spot’ of the DMD gene.