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dc.contributor.advisor Simons, Mikael Prof. Dr.
dc.contributor.author Stündl, Anne-Katrin
dc.date.accessioned 2016-10-28T08:13:12Z
dc.date.available 2016-10-28T08:13:12Z
dc.date.issued 2016-10-28
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002B-7C51-B
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title Characterization of exosomes as a diagnostic marker in neurodegenerative diseases de
dc.type doctoralThesis de
dc.contributor.referee Simons, Mikael Prof. Dr.
dc.date.examination 2016-08-16
dc.description.abstracteng 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. de
dc.contributor.coReferee Schwappach, Blanche Prof. Dr.
dc.contributor.thirdReferee Schneider, Anja PD Dr.
dc.subject.eng exosomes de
dc.subject.eng biomarker de
dc.subject.eng cerebrospinal fluid de
dc.subject.eng neurodegeneration de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7C51-B-2
dc.affiliation.institute Biologische Fakultät für Biologie und Psychologie de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 871375362

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