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Role of presenilins in autophagy and growth factor signaling

dc.contributor.advisorWalter, Jochen
dc.contributor.authorRoeser, Sebastian Philip
dc.date.accessioned2021-02-08T12:42:49Z
dc.date.available2022-02-15T23:00:19Z
dc.date.issued08.02.2021
dc.identifier.urihttps://hdl.handle.net/20.500.11811/8912
dc.description.abstractAlzheimer's disease is the most common neurodegenerative disease and affects millions of people worldwide. To date, no efficient therapies are known for a cure. As people suffering from diabetes mellitus type 2 have an increased risk to develop AD and PS proteins affect autophagy, this study combines these characteristics by further evaluating how γ-secretase/PS proteins affects the autophagy-, insulin- and IGF1-related PI3K/Akt/mTOR signaling pathway.
For that, differentiated SH-SY5Y- and PS-deficient MEF cells were treated with DAPT for pharmacological inhibition of the γ-secretase, as well as starvation medium, insulin or IGF1 for induction of the PI3K/Akt/mTOR signaling pathway. Furthermore, additional pharmacological treatments using rapamycin, bafilomycin A1, 3-MA and chloroquine were performed for further modulations of the pathway.
This study indicates that starvation-induced autophagy affects subcellular distributions of PS proteins as well as subcellular distributions and expression of IGF-R and I-R. Furthermore, PS-deficiency leads to impaired autophagic clearance, lysosomal accumulation and highly impaired phosphorylation of Akt. Most interestingly, impaired autophagic clearance in PS-deficient cells can be highly improved by insulin- and IGF1 treatment. Moreover, the results indicate that all observed dysfunctions depend on PS-expression in a γ-secretase activity- independent manner and most probably independent of Aß generation.
This study successfully demonstrates that PS-deficient cells show a highly impaired adaptation to environmental stress, which might subsequently lead to apoptosis and neurodegeneration independent of Aß generation and γ-secretase activity. However, the exact mechanisms on how PS proteins interact with the PI3K/Akt/mTOR signaling pathway independently of their catalytic activity need to be further elucidated. Moreover, it is still unclear, whether increased autophagic clearance induced by insulin- and IGF1 treatment in PS-deficient cells leads to an improvement of their cellular homoeostasis. Independent of the most preferably pharmacologically targeted Aβ, hyperphosphorylated tau and γ-secretase itself, this study highly indicates the PI3K/Akt/mTOR signaling pathway to be an important target for a possible pharmacological treatment of AD.
en
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectAutophagie
dc.subjectAlzheimer Demenz
dc.subjectInsulin
dc.subjectIGF1
dc.subjectPräsenilin
dc.subjectγ-sekretase
dc.subjectNeurologie
dc.subjectAutophagy
dc.subjectAlzheimer's dementia
dc.subjectPresenilin
dc.subject.ddc570 Biowissenschaften, Biologie
dc.titleRole of presenilins in autophagy and growth factor signaling
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsopenAccess
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-61175
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID6117
ulbbnediss.date.accepted26.01.2021
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereeHofmann, Michael
ulbbnediss.date.embargoEndDate15.02.2022
ulbbnediss.contributor.gnd1252094353


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