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Identifying stage-specific markers of Alzheimer's disease using quantitative proteomics

dc.contributor.advisorChua, John Dr.
dc.contributor.authorYagensky, Oleksandr
dc.date.accessioned2018-09-13T09:07:48Z
dc.date.available2018-09-13T09:07:48Z
dc.date.issued2018-09-13
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-002E-E4A6-D
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-7052
dc.language.isoengde
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc572de
dc.titleIdentifying stage-specific markers of Alzheimer's disease using quantitative proteomicsde
dc.typedoctoralThesisde
dc.contributor.refereeChua, John Dr.
dc.date.examination2018-06-26
dc.description.abstractengAlzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to progressive memory loss and impairment of other cognitive functions. It is the most prevalent form of dementia in the elderly and is estimated to affect 20 to 45 million people worldwide. The incidences are expected to rise sharply over the coming decades with no effective therapeutics available to combat the disease. Recent advances in AD research uncovered many important aspects of the disorder. Nevertheless, the AD progression at the molecular level, particularly at its early stage, remains elusive. In this thesis I investigated the changes in the brain proteome and phosphoproteome over the course of neurodegeneration in a triple transgenic mouse model of AD (3×Tg-AD). Bioinformatic analysis of stage-specific alterations in protein expression and phosphorylation allowed to determine the affected biological functions along the progression of the disorder. Notably, proteins related to apoptotic response, mitochondria function and synaptic transmission were among the most affected groups in the early stages of AD. Several proteins in the dataset exhibited strong expression change before the AD onset in 3×Tg-AD mice. These proteins can be considered as putative presymptomatic brain markers of AD and pose a special interest for their potential in early diagnosis and treatment of AD. Closer investigation of one such marker, heme-binding protein 1 (Hebp1), revealed its increased expression in the brains of patients affected by rapidly-progressing forms of AD. Furthermore, Hebp1 is found to be expressed predominantly in neurons where it exhibits a perimitochondrial localization and interacts with the mitochondrial contact site and cristae organizing system (MICOS) complex. Remarkably, genetic depletion of Hebp1 reduces apoptosis induced by excessive levels of heme. Importantly, abnormalities in heme metabolism and disturbance of brain vasculature were previously reported in AD. Collectively, my findings suggest that the increase in Hebp1 expression early in AD progression can be linked to impaired heme metabolism and neuronal loss.de
dc.contributor.coRefereeKlopfenstein, Dieter Dr.
dc.subject.engAlzheimer's diseasede
dc.subject.engProteomicsde
dc.subject.eng3xTg-ADde
dc.subject.engCell deathde
dc.subject.engHemede
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-002E-E4A6-D-6
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn103082097X


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