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@PHDTHESIS{Islam:282310,
      author       = {Islam, Rezaul},
      title        = {{E}pigenetic {B}iomarker and {T}herapeutic {I}ntervention
                      for {D}ementia},
      school       = {Georg-August-Universität Göttingen},
      type         = {Dissertation},
      reportid     = {DZNE-2025-01280},
      pages        = {126 p.},
      year         = {2021},
      note         = {Dissertation, Georg-August-Universität Göttingen, 2021},
      abstract     = {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.},
      cin          = {AG Fischer},
      cid          = {I:(DE-2719)1410002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://pub.dzne.de/record/282310},
}