Epigenetic Biomarker and Therapeutic Intervention for Dementia
by Md Rezaul Islam
Date of Examination:2019-10-30
Date of issue:2021-01-11
Advisor:Prof. Dr. André Fischer
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Dr. Camin Dean
Persistent Address:
http://dx.doi.org/10.53846/goediss-8394
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Description:Cumulative Doctoral Thesis
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Abstract
English
Dementia is the most significant health challenge in modern times, currently affecting over 50 million people worldwide. The number of people afflicted with this disorder is on the rise and expected to double by 2025. Causative and symptomatic treatments of this disease have been so far unsuccessful.This is partly due to the fact that patients are only diagnosed with dementia at an advanced stage, when a massive neuronal loss has already manifested. There is substantial evidence memory impairment is preceded by molecular changes that happen years before the onset of cognitive decline. Therefore, there is an urgent need for biomarkers to diagnose early changes in the brain, which would allow clinicians to intervene therapeutically at an earlier phase of the disease. Moreover, it is equally important to study the underlying mechanisms of risk factors that might precipitate these early changes in the brain. Management of those risk factors may significantly reduce the progression of dementia or even prevent the onset of the disease. Therefore, in this cumulative thesis, I first tested the hypothesis that microRNAs in blood could be potential early diagnostic biomarkers for dementia. By using human cross-sectional and mouse longitudinal data, coupled with advanced multi-step systems biology approach, I report a blood-based “microRNA signature” that can inform about early cognitive decline in healthy and pathological conditions. Intriguingly, by manipulating the level of one of the signature microRNAs, I could improve memory in cognitively impaired mice. These data suggest that the “microRNA signature” that I report can not only be used as a diagnostic marker but also as a therapy to manage cognitive deficits in early dementia. In addition, I investigated how cardiac failure, a risk factor of dementia, could affect brain functions at the molecular level. By using transgenic mice with failing hearts, I report down-regulation of memory-related genes in the hippocampus leads to cognitive deficits in transgenic mice. Analyses of genome-wide distribution of H3K4me3 reveal that reduced levels of H3K4me3 at the promoters of genes may underpin cognitive changes. Consistently, through oral administration of SAHA, an inhibitor of HDAC, I delineate that the observed cognitive deficits can be rescued. At the molecular level, SAHA could partially restore both microRNAome and RNAome, highlighting its potential as a therapeutic intervention to ameliorate cognitive deficits following heart failure. Both of these studies provide key insight to molecular underpinnings and therapeutic interventions of early dementia. While epigenetic biomarker based on microRNAs could be useful to stratify individuals at risk of developing dementia, epigenetic drugs could be suitable strategy to restore memory and attenuate the future risk of dementia.
Keywords: microRNA; brain plasticity; dementia; biomarker; heart failure; vorinostat; epigenetic rescue; epigenetic modification; Alzheimer; HDAC inhibitor
