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Characterization of epigenetic and transcriptional changes in aging and Alzheimer’s disease

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Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica

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[eng] 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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[spa] Los cambios epigenéticos son reconocidos como parte del proceso de envejecimiento y están implicados en muchas enfermedades relacionadas con la edad, como la enfermedad de Alzheimer (EA). Estos mecanismos regulan la expresión génica de una manera estable y potencialmente reversible, sin alterar la secuencia primaria del ADN. Incluyen principalmente la metilación del ADN, modificaciones post-traduccionales de histonas, y ARNs no codificantes. Por otro lado, se ha estimado que alrededor de 1/3 de los casos de EA podría ser atribuible a factores de riesgo relacionados con el estilo de vida. De hecho, se ha reportado que muchos nutrientes ejercen un efecto favorable o desfavorable por lo que respecta al desarrollo o progresión de la EA a través de mecanismos epigenéticos. Del mismo modo, también se ha descrito una modulación de estos mecanismos por el ejercicio físico en el sistema nervioso central, destacando sus beneficios. En este contexto, la siguiente tesis contiene tres estudios que tienen como objetivo mejorar la comprensión de la contribución de estos mecanismos al envejecimiento patológico y la EA, estudiar su papel en la orquestación de los efectos inducidos por el ejercicio físico y una deficiencia en folatos en la salud del cerebro, y su potencial como biomarcadores precoces de la EA. En el primer estudio se midieron los niveles plasmáticos de microARNs en muestras de pacientes con EA, sujetos preclínicos de la enfermedad (con capacidades cognitivas intactas, pero niveles alterados de beta-amiloide en líquido cefalorraquídeo) y controles sanos de edad avanzada. Los microARNs miR-34a-5p y miR-545-3p destacaron como posibles biomarcadores tempranos de la EA. En el segundo estudio, se detectaron alteraciones en microARNs, genes reguladores de acetilación de histonas y niveles globales de acetilación de histona 3 en hipocampo de ratones SAMP8 de 10 meses de edad (un modelo de ratón de senescencia acelerada con características similares a la EA). Además, se observó que algunos de estos parámetros fueron modulados, y en algunos casos restaurados, por una intervención de 8 semanas de ejercicio voluntario. En el último estudio se caracterizaron cambios de comportamiento, epigenéticos, y transcripcionales, asociados a una deficiencia en folatos en ratones de 10 meses. En consecuencia, se planteó su posible relación con el mayor riesgo de neurodegeneración observado en este tipo de deficiencias.

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Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèutica

# metadata.dc.title[].value
Characterization of epigenetic and transcriptional changes in aging and Alzheimer’s disease