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@PHDTHESIS{Stndl:144819,
      author       = {Stündl, Anne-Katrin},
      title        = {{C}haracterization of exosomes as a diagnostic marker in
                      neurodegenerative diseases},
      school       = {Georg-August-Universität zu Göttingen},
      type         = {Dissertation},
      reportid     = {DZNE-2020-00261},
      pages        = {95 pages : illustrations, XII},
      year         = {2016},
      note         = {Dissertation, Georg-August-Universität zu Göttingen,
                      2016},
      abstract     = {α-Synuclein pathology has been hypothesized to propagate
                      in synucleinopathies by intercellular transfer of pathogenic
                      seeds in a prion-like fashion. Extracellular release of
                      α-Synuclein via small extracellular vesicles has been
                      proposed as one of the mechanisms of cell-to-cell disease
                      transmission. In vitro, extracellular α-Synuclein has been
                      detected in exosomal vesicles and we have recently provided
                      evidence that α-Synuclein is present in exosomes in the
                      central nervous system in vivo. We hypothesized that
                      exosomes from patients with α Synuclein related
                      neurodegeneration serve as carriers for interneuronal
                      disease transfer. In this study, we purified exosomes from
                      cerebrospinal fluid from patients with synucleinopathies
                      including Parkinson`s disease and dementia with Lewy bodies,
                      progressive supranuclear palsy as an example of a disease
                      that clinically overlaps with Parkinson`s disease but
                      without underlying α-Synuclein pathology and other
                      neurological controls without neurodegenerative diseases.
                      Exosome numbers and exosomal α-Synuclein levels were
                      quantified and their potential to induce aggregation of
                      soluble α-Synuclein was evaluated. We observed differences
                      in cerebrospinal fluid exosomal α-Synuclein levels between
                      patients with Parkinson`s disease and dementia with Lewy
                      bodies and between dementia with Lewy bodies and controls.
                      In addition, exosomal α-Synuclein levels correlated with
                      cognitive decline and Tau levels as a marker of
                      neurodegeneration in dementia with Lewy bodies. By analyzing
                      exosomal α-Synuclein levels and exosome numbers, we were
                      able to distinguish Parkinson`s disease from dementia with
                      Lewy bodies and controls as well as dementia with Lewy
                      bodies from Parkinson`s disease and controls with high
                      sensitivity and specificity. Importantly, cerebrospinal
                      fluid exosomes from Parkinson`s disease and dementia with
                      Lewy bodies disease patients induced aggregation of
                      α-Synuclein in a reporter cell model, dependent on the
                      amount of exosomal α-Synuclein. Thus, exosomal α-Synuclein
                      could serve as a diagnostic biomarker for α-Synuclein
                      related neurodegenerative diseases and as a progression
                      marker in dementia with Lewy bodies. These findings further
                      indicate that cerebrospinal fluid derived exosomes from
                      patients with Parkinson`s disease and dementia with Lewy
                      bodies contain a pathogenic α-Synuclein species, which
                      induces aggregation of endogenous α-Synuclein in recipient
                      neurons and therefore could transmit disease pathology.
                      Since multiple recent therapy trials in Alzheimer`s disease
                      have failed and therapeutic interventions are most promising
                      in early and even preclinical stages, the accurate
                      identification of patients with Alzheimer`s disease is
                      indispensable. Therefore, diagnostic and prognostic
                      biomarkers are required and identification of such markers
                      would also give insight into the underlying molecular
                      mechanisms of Alzheimer`s disease pathology. Accumulating
                      evidence suggests that dysregulation of processes, which
                      physiologically regulate gene expression, plays an important
                      role in the pathogenesis of neurodegenerative diseases.
                      Additionally, dysregulation of small non-coding RNAs in
                      Alzheimer`s disease brain has been shown in various studies.
                      In our second study, we analyzed the small non-coding RNA
                      composition of exosomes derived from human cerebrospinal
                      fluid in order to test whether exosomal small non-coding RNA
                      profiles can be used as a disease signature for Alzheimer`s
                      disease. Here, we show that genome-wide profiling of
                      cerebrospinal fluid exosomal small non-coding RNA expression
                      reveals a specific small RNA signature which differentiates
                      Alzheimer`s disease from cognitive healthy controls. Thus,
                      our selected set of exosomal small non-coding RNAs could be
                      used as a potential biomarker in the future, replication in
                      a larger validation cohort provided.},
      cin          = {AG Schneider Göttingen},
      cid          = {I:(DE-2719)1440011},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.53846/goediss-5944},
      url          = {https://pub.dzne.de/record/144819},
}