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@PHDTHESIS{Zhou:282313,
      author       = {Zhou, Jiayin},
      title        = {{G}ene-expression control in early and late-onset dementia},
      school       = {Georg-August-Universität Göttingen},
      type         = {Dissertation},
      reportid     = {DZNE-2025-01283},
      pages        = {155 p.},
      year         = {2022},
      note         = {Dissertation, Georg-August-Universität Göttingen, 2022},
      abstract     = {Mutations in genes that control epigenetic gene expression,
                      especially the machinery that controls Histone 3 lysine 4
                      (H3K4me) methylation, are over-represented in intellectual
                      disability disorders. It is mediated by both lysine
                      methyltransferases and demethylases. Dysregulation of these
                      enzymes is closely associated with cognitive dysfunction in
                      humans. Moreover, there is evidence that H3K4me3 levels
                      decrease in neurodegenerative diseases such as Alzheimer’s
                      disease and previous studies demonstrated that H3K4me
                      demethylases (KDMs) are important targets for cognitive
                      functions. In the first study, we specifically tested the
                      therapeutic potential of H3K4me demethylases (KDMs) in vitro
                      and in vivo. Our data suggest that decreasing the levels of
                      KMD5B can improve neuronal synapse plasticity and reduce
                      inflammatory responses. When we downregulated the KDM5B in
                      aged mice, it helps to rescue their learning and memory
                      abilities. Furthermore, inhibition of KDM5B in mouse models
                      for age-associated memory decline or amyloid deposition also
                      ameliorated memory impairment. Our data strongly suggest
                      that H3K4me demethylases, represented by KDM5B, have great
                      potential to become therapeutic targets for the treatment of
                      cognitive disorders. Additionally, Frontotemporal
                      degeneration is the second most common type after
                      Alzheimer’s disease, sharing pathophysiological mechanisms
                      and genetic origins with some dementia-specific disorders.
                      Mining FTD-associated microRNAs can be used to distinguish
                      FTD from other dementia-specific disorders. Thus in the
                      second study, we established an in-depth smallRNAome
                      sequencing analysis of frontal and temporal cortex tissue to
                      identify specific microRNAs that showed dysregulation in a
                      group of FTD patients. Further analysis was performed by
                      manipulating one of these signatures, miR-129-5p, to reflect
                      the molecular changes that occur during brain pathology in
                      vitro. The impact of inhibition of miR-129-5p markers on
                      cognitive impairment was also revealed in animals,
                      suggesting its use as a powerful pathogenetic indicator of
                      FTD-related disorders.},
      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/282313},
}