Characterization of epigenetic and transcriptional changes in aging and Alzheimer’s disease
Epigenetic changes are currently recognized as part of the aging process and have been implicated in many age-related chronic diseases such as Alzheimer’s disease (AD). The term epigenetics includes a variety of processes known to regulate gene expression in a stable and potentially reversible way,...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/401499 |
| Acceso en línea: | http://hdl.handle.net/10803/401499 |
| Access Level: | acceso abierto |
| Palabra clave: | Malaltia d'Alzheimer Enfermedad de Alzheimer Alzheimer's disease Epigènesi Epigenesis Exercici Ejercicio físico Exercise Envelliment Envejecimiento Aging Ciències de la Salut 615 |
| Sumario: | Epigenetic changes are currently recognized as part of the aging process and have been implicated in many age-related chronic diseases such as Alzheimer’s disease (AD). The term epigenetics includes a variety of processes known to regulate gene expression in a stable and potentially reversible way, without altering the primary DNA sequence. The molecular mechanisms that mediate epigenetic regulation are principally DNA methylation, post-translational modifications of histones, and regulation by non-coding RNAs. Research on age-related disorders have recently focused in epigenetic mechanisms since they allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and a growing number of epigenetic alterations in AD have been described recently. Interestingly, it has been estimated that about one-third of AD dementia cases worldwide might be attributable to modifiable risk factors including depression, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and low education; whereas investigations like the FINGER study, a two-year landmark randomized controlled trial, show that a multicomponent approach targeting several vascular and lifestyle-related risk factors simultaneously in elderly people at risk of dementia can improve or maintain cognitive functioning. In fact, many nutrients or dietary compounds (including folate, vitamin B-12, curcumin, resveratrol, selenium, etc.) are described to exert a favorable or unfavorable effect regarding AD onset and progression through epigenetic mechanisms. Similarly, several studies have described a modulation of these mechanisms by physical exercise on different animal peripheral systems and central nervous system, highlighting beneficial epigenetic exercise-induced effects. Within this context, this thesis comprises three studies aiming to better understand the epigenetic contribution to pathological aging, the potential utility of epigenetic changes as early biomarkers of AD, and their role in orchestrating physical exercise and folate deficiency effects on brain health. In the first study we measured plasma miRNA levels in samples from AD patients, AD preclinical subjects (patients with intact cognitive abilities but β-amyloid levels <500pg/mL in cerebrospinal fluid), and healthy elderly controls. We found that plasma miR-34a and miR-545-3p showed good diagnostic values in our first cohort and so they could constitute good early peripheral biomarkers for AD. However, contradictory results regarding a second cohort highlights possible sources of variability in miRNA analysis (e.g. age or environmental factors), which currently prevents their use as reliable clinical tools and warrants further research on the topic. In the second study, we found alterations on twenty-one microRNAs (previously reported to be involved in aging and neurodegeneration), histone-acetylation regulatory genes (histone deacetylases HDAC5, HDAC6, and SIRT1), and global histone H3 acetylation levels in the hippocampus of 10-month-old SAMP8 mice (a senescence-accelerated mouse model resembling features of AD), compared to SAMR1 control mice. We also observed that some of these parameters were modulated by 8 weeks of voluntary exercise; particularly, seven microRNAs (involved in the regulation of signaling pathways previously reported to be modulated in the brain by exercise), histone deacetylases HDAC3, HDAC5, and histone H3 acetylation levels. In fact, acetylation levels of histone H3, which have been described to positively correlate with cognitive function, were reduced in SAMP8 hippocampus, and the physical exercise intervention was able to restore its levels. Finally, in the last study we characterized epigenetic and transcriptional changes associated with folate metabolism disruption on 10-month old mice, and its potential impact on brain neurodegeneration and cognition. We found that dietary and/or genetic folate metabolism disruption leads to alterations on short-term recognition memory, brain gene expression of APP-processing enzymes, neurotrophic factors, histone-acetylation and DNA methylation regulatory enzymes. Particularly, dysregulation of both the neurotrophic factor Bdnf and the APP-processing enzyme Psen1, seems to be associated with changes on DNA methylation levels at their gene promoters. We concluded that this signature may be contributing to the higher neurodegeneration risk reported in dietary and genetic folate-deficiencies. |
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