Exploring the potential pathogenic mechanism of Alzheimer’s disease through in silico analysis of gamma secretase
Background: Alzheimer`s disease (AD) is a progressive neurologic disorder that causes brain atrophy and neuronal cell death which in turn manifests as dementia. In later stages of the disease patients are unable to care for themselves. This alongside the high number of people affected, makes AD the...
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| Format: | Master Thesis |
| Language: | English |
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Sveučilište u Rijeci. Odjel za biotehnologiju.
2021
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| Online Access: | https://www.unirepository.svkri.uniri.hr/islandora/object/biotechri:591 https://urn.nsk.hr/urn:nbn:hr:193:425815 https://www.unirepository.svkri.uniri.hr/islandora/object/biotechri:591/datastream/PDF |
| Summary: | Background: Alzheimer`s disease (AD) is a progressive neurologic disorder that causes brain atrophy and neuronal cell death which in turn manifests as dementia. In later stages of the disease patients are unable to care for themselves. This alongside the high number of people affected, makes AD the most expensive condition for health care providers in the industrialized nations. The pathogenic processes underlining AD usually occur through dysregulation of amyloid-β (Aβ) processing. The transmembrane protease responsible for Aβ cleavage is Gamma-secretase. All current attempts to cure AD trough regulation of γ-secretase have resulted in little to no observed effect on the pathogenesis of the disease. This miss in drug creation is caused by a lack of information regarding understanding Aβ formation. Better knowledge of the factors involved in Aβ processing is needed. Experimental: Gamma-secretase structures at 3.4 angstrom resolution were analyzed using multiscale molecular dynamic approaches and electrostatic calculations. Results: Multiscale molecular dynamics can describe structural interactions that occur in the binding of C99-CTFβ to the γ-secretase complex. C99-CTFβ is capable of docking near the active site disrupting substrate processing. Such interactions can partially or fully inhibit gamma-secretase or shift the proteolytic cleavages from the Aβ 40 path to the neurotoxic Aβ 42. Nicastrine can exist in an open or a closed form. The closed form prevents substrates from interacting, preventing the disruption of the active site. Conclusion: Through substrate oversaturation, interactions can lead to a change in the mechanism and precision of Aβ cleavage. This can drive pathogenic processes in AD. Pozadina: Alzheimerova bolest (AD) je progresivni neurološki poremećaj koji uzrokuje atrofiju mozga i smrt neuronskih stanica što se zauzvrat očituje kao demencija. U kasnijim fazama bolesti, pacijenti nisu u stanju brinuti sami za sebe. To zajedno s velikim brojem pogođenih ljudi, čini AD najskupljom bolesti za ... |
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