The role of Gingko biloba extract on autophagy modulation, protein clearance and neuronal cell death in an in vitro model of Alzheimer's disease

Khoza, Akile (2019-03)

Thesis (MSc)--Stellenbosch University, 2019.


ENGLISH ABSTRACT: Introduction: Alzheimer’s disease (AD) is a complex neurological disease, characterized by two protein aggregate forms, namely extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of tau protein. AD is the most common type of progressive dementia and is currently poorly treated, which is associated with poor clinical outcomes. Although significant insight has been gained regarding AD pathology, limited progress has been made in the development of pharmaceutical therapeutics that modify or reverse the debilitating effects of this disease. Autophagy is a vital process involved in cellular survival, as it is essential for organelle and long-lived protein turnover. As such, it is widely accepted that autophagy impairment is a major contributing factor in the development of AD. Gingko biloba (GB) and lithium chloride (LiCl) have been reported to be neuroprotective in the context of neurodegenerative diseases. Even though some countries readily prescribe GB and LiCl to individuals suffering from AD, their mechanism of action, their potency in enhancing autophagy and their ability to clear toxic protein aggregates remains largely unclear. We hypothesized that treatment with GB will exhibit a concentration dependent effect on autophagic activity, and this effect will be further enhanced through combination treatment with LiCl. This effect may then translate in the distinct removal of amyloid precursor protein (APP) and Aβ, preserving lysosomal function and mitochondrial integrity. The aim of the proposed study was therefore to investigate the effect of both GB and LiCl as a single or combination treatment intervention on the modulation of autophagy activity, and the mitigation of Aβ proteotoxicity in an in vitro model of AD.

AFRIKAANSE OPSOMMING: Inleiding: Alzheimer-siekte (AS) is ‘n komplekse neurologiese siekte, gekarakteriseer deur twee proteïen aggregate, naamlik ekstrasellulêre amiloïed-beta (Aβ) plaak en intrasellulêre neurofibrilêre voue van tau proteïen. AS is die mees algemene tipe progressiewe demensie, word huidiglik swak behandel en is bekend vir swak kliniese uitkomste. Alhoewel beduidende kennis opgedoen is wat AS patologie betref, is daar beperkte vordering in terme van die ontwikkeling van farmaseutiese terapie wat die aftakelende uitwerking van die siekte verander of om keer. Outofagie is ‘n noodsaaklik proses betrokke in die oorlewing van selle aangesien dit noodsaaklik is vir organel en langlewende proteïen omset. As sulks word dit oor die algemeen aanvaar dat outofagie disfunksie ‘n groot rolspeler is in die ontwikkeling van AS. Vorige bevindinge dui daarop dat Gingko biloba (GB) en litium chloried (LiCl) ‘n neurobeskermende effek het in die konteks van neurodegeneratiewe siektes. Alhoewel sommige lande geredelik GB en LiCl voorskryf aan individue wat lei aan AS, is dit steeds onduidelik hoe hierdie middele op ‘n meganistiese vlak te werk gaan om die siekte te beveg en tot watter mate hul outofagie versnel en toksiese proteïen aggregate verwyder. Ons stel voor dat behandeling met GB ‘n konsentrasie afhanklike effek op outofagie aktiwiteit sal toon en dat hierdie effek verder versnel sal word in kombinasie met LiCl. Hierdie effek kan moontlik oorgedra word tot die verwydering van amiloïed voorganger proteïen en Aβ wat lei tot die behoud van lisosomale funktionaliteit en mitochondriale integriteit. Die doel van die voorgelegde studie is dus om te ondersoek wat die effek van GB en LiCl, beide op hul eie sowel as in kombinasie, sal wees op die modulasie van outofagie aktiwiteit en op die verlaging van Aβ proteotoksisiteit in ‘n in vitro model van AS.

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