ABSTRACT
BACKGROUND AND OBJECTIVES: There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. METHODS: A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. RESULTS: The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE É4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. DISCUSSION: These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. REGISTRATION INFORMATION: Research Ethics Committee of the University Hospital of Navarre (PI17/02218).
Subject(s)
Alzheimer Disease , Humans , Female , Aged , Male , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/pathology , DNA Methylation/genetics , Case-Control Studies , Biomarkers , Genotype , tau Proteins/genetics , Amyloid beta-Peptides/geneticsABSTRACT
La hospitalización a domicilio (HAD) es una alternativa asistencial del Área de Salud de Pamplona consistente en un modelo organizativo capaz de dispensar a pacientes en su propiodomicilio un conjunto de actividades y cuidados sanitarios con complejidad, intensidad y duración comparables a los de una hospitalización convencional cuando todavía precisan de unavigilancia activa y una asistencia compleja. Ante el incremento progresivo de ingresos en el Hospital Universitario de Navarra (HUN) y lasprevisiones existentes para las siguientes semanas, el lunes 9 de marzo de 2020 se decide creardentro de la unidad de HAD del HUN una unidad específica centrada en COVID-19 y que, portanto, entra en el dispositivo de atención a los pacientes con infección por COVID-19. Debido al incremento progresivo en el número de ingresos hospitalarios, el día 26 de marzo elServicio Navarro de Salud-Osasunbidea (SNS-O) decide medicalizar el hotel Iruña Park con elobjetivo de incrementar el número de camas hospitalarias disponibles. En este documento se expone la actividad realizada en las tres primeras olas por la unidad deHAD del HUN en la atención domiciliaria y en la primera ola en el hotel medicalizado.(AU)
Subject(s)
Humans , Home Care Services, Hospital-Based , Hospitals, University , Pandemics , Coronavirus Infections/epidemiology , Spain , Public Health , Health ServicesABSTRACT
The discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies. ABBREVIATIONS: AD: Alzheimer's disease; DMPs: Differentially methylated positions; CSF: Cerebrospinal fluid; ßA42: ß-amyloid 42; PET: positron emission tomography; 5mC: 5-methyl cytosine; CpG: cytosine-guanine dinucleotides; ANK1: ankyrin-1; BIN1: amphiphysin II; p-tau: hyperphosphorylated tau; CERAD: Consortium to Establish A Registry for Alzheimer's Disease; SD: standard deviation; ANOVA: one-way analysis of variance; VLCFAs: very long-chain fatty acids; DHA: docosahexaenoic acid; mTOR: mechanistic target of rapamycin.
Subject(s)
Alzheimer Disease/genetics , DNA Methylation , Epigenesis, Genetic , Hippocampus/metabolism , Alzheimer Disease/pathology , Aspartate Aminotransferase, Cytoplasmic/genetics , Fatty Acid Elongases/genetics , Hippocampus/pathology , Histones/genetics , Humans , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
BACKGROUND: Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays. RESULTS: Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs. CONCLUSIONS: These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.
Subject(s)
Alzheimer Disease/genetics , DNA Methylation , Genes, Homeobox , Hippocampus/chemistry , Neurogenesis , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Cadaver , Case-Control Studies , Epigenesis, Genetic , Female , Genome-Wide Association Study/methods , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Phosphorylation , Promoter Regions, Genetic , tau Proteins/metabolismABSTRACT
Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by RT-qPCR in Alzheimer's disease (AD) patients and controls in the hippocampus, the core of tau pathology in the brain. LMNA, LMNB1, and LMNB2 genes showed moderate mRNA levels in the human hippocampus with highest expression for the LMNA gene. Moreover, LMNA mRNA levels were increased at the late stage of AD (1.8-fold increase; p-value < 0.05). In addition, a moderate positive correlation was found between age and LMNA mRNA levels (Pearson's r = 0.581, p-value = 0.018) within the control hippocampal samples that was not present in the hippocampal samples affected by AD. A-type and B-type lamin genes are expressed in the human hippocampus at the transcript level. LMNA mRNA levels are up-regulated in the hippocampal tissue in late stages of AD. The effect of age on increasing LMNA expression levels in control samples seems to be disrupted by the development of AD pathology.
Subject(s)
Alzheimer Disease/genetics , Gene Expression Regulation , Hippocampus/metabolism , Lamin Type A/genetics , Adult , Age Factors , Aged , Aged, 80 and over , Female , Humans , Lamin Type A/metabolism , Male , Middle Aged , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , tau Proteins/metabolismABSTRACT
Lamina-associated polypeptide 1 (LAP1) is an integral protein of the inner nuclear membrane that has been implicated in striated muscle maintenance. Mutations in its gene have been linked to muscular dystrophy and cardiomyopathy. As germline deletion of the gene encoding LAP1 is perinatal lethal, we explored its potential role in myogenic differentiation and development by generating a conditional knockout mouse in which the protein is depleted from muscle progenitors at embryonic day 8.5 (Myf5-Lap1CKO mice). Although cultured myoblasts lacking LAP1 demonstrated defective terminal differentiation and altered expression of muscle regulatory factors, embryonic myogenesis and formation of skeletal muscle occurred in both mice with a Lap1 germline deletion and Myf5-Lap1CKO mice. However, skeletal muscle fibres were hypotrophic and their nuclei were morphologically abnormal with a wider perinuclear space than normal myonuclei. Myf5-Lap1CKO mouse skeletal muscle contained fewer satellite cells than normal and these cells had evidence of reduced myogenic potential. Abnormalities in signalling pathways required for postnatal hypertrophic growth were also observed in skeletal muscles of these mice. Our results demonstrate that early embryonic depletion of LAP1 does not impair myogenesis but that it is necessary for postnatal skeletal muscle growth.
Subject(s)
Carrier Proteins/physiology , Membrane Proteins/physiology , Muscle Development/genetics , Muscle, Skeletal/cytology , Muscular Dystrophies/embryology , Myoblasts/cytology , Animals , Cell Differentiation , Cell Proliferation , Female , Gene Expression Regulation, Developmental , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/metabolism , Myoblasts/metabolism , Myogenic Regulatory FactorsABSTRACT
La metilación del ADN es un mecanismo epigenético que controla la expresión génica. En la enfermedad de Alzheimer (EA) se ha encontrado hipometilación global del ADN en neuronas del córtex cerebral humano. Además, se han identificado variaciones en el patrón de metilación de genes candidatos en el tejido cerebral entre pacientes y controles, como el gen PSEN1 y APOE, relacionados con la fisiopatología de la EA. En otras demencias degenerativas también se han descrito variaciones en la metilación de genes clave, como hipometilación del gen SNCA en la enfermedad de Parkinson y la demencia con cuerpos de Lewy o hipermetilación del promotor del gen GRN en la demencia frontotemporal. Algunas de estas variaciones en el patrón de metilación del ADN son compartidas por el tejido cerebral y la sangre periférica. Este hallazgo permitirá su utilización como biomarcadores epigenéticos en el diagnóstico de las enfermedades neurodegenerativas (AU)
DNA methylation is an epigenetic mechanism that controls gene expression. In Alzheimer's disease (AD), global DNA hypomethylation of neurons has been described in the human cerebral cortex. Moreover, several variants in the methylation pattern of candidate genes have been identified in brain tissue when comparing AD patients and controls. Specifically, DNA methylation changes have been observed inPSEN1 and APOE, both genes previously being involved in the pathophysiology of AD. In other degenerative dementias, methylation variants have also been described in key genes, such as hypomethylation of the SNCA gene in Parkinson's disease and dementia with Lewy bodies or hypermethylation of the GRN gene promoter in frontotemporal dementia. The finding of aberrant DNA methylation patterns shared by brain tissue and peripheral blood opens the door to use those variants as epigenetic biomarkers in the diagnosis of neurodegenerative diseases (AU)
Subject(s)
Humans , Epigenesis, Genetic , Alzheimer Disease/genetics , DNA Methylation/genetics , Dementia/genetics , Gene Expression/genetics , Nervous System Diseases/geneticsABSTRACT
DNA methylation is an epigenetic mechanism that controls gene expression. In Alzheimer's disease (AD), global DNA hypomethylation of neurons has been described in the human cerebral cortex. Moreover, several variants in the methylation pattern of candidate genes have been identified in brain tissue when comparing AD patients and controls. Specifically, DNA methylation changes have been observed in PSEN1 and APOE, both genes previously being involved in the pathophysiology of AD. In other degenerative dementias, methylation variants have also been described in key genes, such as hypomethylation of the SNCA gene in Parkinson's disease and dementia with Lewy bodies or hypermethylation of the GRN gene promoter in frontotemporal dementia. The finding of aberrant DNA methylation patterns shared by brain tissue and peripheral blood opens the door to use those variants as epigenetic biomarkers in the diagnosis of neurodegenerative diseases.
Subject(s)
Alzheimer Disease/genetics , DNA Methylation , Epigenesis, Genetic , Dementia/genetics , Genetic Markers , HumansABSTRACT
X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.
Subject(s)
Membrane Proteins/metabolism , Muscle, Skeletal/metabolism , Nuclear Proteins/metabolism , TNF Receptor-Associated Factor 3/metabolism , Animals , Cells, Cultured , Cytoskeletal Proteins , Fibroblasts/metabolism , Gene Deletion , HEK293 Cells , Hepatocytes/metabolism , Humans , Liver/metabolism , Liver/physiology , Membrane Proteins/genetics , Mice , Muscle, Skeletal/pathology , Muscular Dystrophy, Emery-Dreifuss/genetics , Muscular Dystrophy, Emery-Dreifuss/metabolism , Nuclear Proteins/genetics , Protein Binding , TNF Receptor-Associated Factor 3/geneticsABSTRACT
Laminopathies are a group of diseases that share wrong codification of lamins, building proteins of the nuclear lamina. Different tissues are affected in those disorders: striated muscle, adipose tissue, central or peripheral nervous system and aging process. Emery-Dreifuss muscular dystrophy and Hutchinson-Gildford Progery Syndrome are two examples of laminopathies.Other diseases, due to mutations in different genes, impair lamins function by a direct or an indirect way and they are frequently considered together.The last decade has seen an increasing interest and scientific advances on laminopathies that will allow us to answer key questions regarding metabolism, insulin resistance, sudden death and aging. Laminopathies are reviewed in this article from a molecular, pathogenic and clinical point of view (AU)
Las laminopatías son un conjunto de enfermedades raras que comparten formas erróneas de codificación genética de las láminas, proteínas constitutivas de la lámina nuclear. Son trastornos que afectan a diferentes tejidos y funciones como el tejido muscular estriado, el tejido adiposo, el tejido óseo, el sistema nervioso o el envejecimiento precoz. La distrofia muscular de Emery-Dreifuss o el síndrome Hutchinson-Gildford Progeria son ejemplos de laminopatías. Conjuntamente con ellas suelen estudiarse otros trastornos que provocan de forma directa o indirecta alteración de la función de las láminas. El creciente interés y estudio que las laminopatías han suscitado desde hace una década podrían permitir encontrar respuestas a preguntas clave en relación con el metabolismo, la resistencia a la insulina, la muerte súbita o el envejecimiento. En este trabajo se revisan las laminopatías desde un punto de vista molecular, patogénico y clínico (AU)
Subject(s)
Humans , Nuclear Lamina/genetics , Nuclear Envelope/genetics , Rare Diseases/epidemiology , Muscular Dystrophy, Emery-Dreifuss/genetics , Progeria/genetics , Muscular Diseases/genetics , Cardiomyopathies/genetics , Insulin Resistance , Lipodystrophy/genetics , Aging, Premature/geneticsABSTRACT
In the past decade, the inner nuclear membrane has become a focus of research on inherited diseases. A heterogeneous group of genetic disorders known as laminopathies have been described that result from mutations in genes encoding nuclear lamins, intermediate filament proteins associated with the inner nuclear membrane. Mutations in genes encoding integral inner nuclear membrane proteins, many of which bind to nuclear lamins, also cause diseases that sometimes are very similar to those caused by lamin gene mutations. The pathogenic mechanisms that underlie these diseases, which often selectively affect different tissues or organ systems despite the near-ubiquitous expression of the proteins, are only beginning to be elucidated. The unfolding story of the laminopathies provides a remarkable example of how research in basic cell biology has impacted upon medicine and human health.
Subject(s)
Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/physiopathology , Membrane Proteins/genetics , Models, Biological , Nuclear Envelope/metabolism , Nuclear Lamina/genetics , Amino Acid Sequence , Humans , Molecular Sequence Data , Mutation/geneticsABSTRACT
Laminopathies are a group of diseases that share wrong codification of lamins, building proteins of the nuclear lamina. Different tissues are affected in those disorders: striated muscle, adipose tissue, central or peripheral nervous system and aging process. Emery-Dreifuss muscular dystrophy and Hutchinson-Gildford Progery Syndrome are two examples of laminopathies. Other diseases, due to mutations in different genes, impair lamins function by a direct or an indirect way and they are frequently considered together. The last decade has seen an increasing interest and scientific advances on laminopathies that will allow us to answer key questions regarding metabolism, insulin resistance, sudden death and aging. Laminopathies are reviewed in this article from a molecular, pathogenic and clinical point of view.