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Selected Publication:
Krassnig, S.
Effects of ß-Synuclein overexpression in a transgenic animal model of Alzheimer’s disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Authors Med Uni Graz:
- Kraßnig Stefanie
- Advisor:
- Schreibmayer Wolfgang
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- Abstract:
- Synucleins (Syn) are a highly conserved protein family comprising three members: a-, ß- and ¿-Syn. a-Syn is the most prominent family member as it accumulates in the so called Lewy Bodies, the major pathological hallmark of Parkinson’s disease. Parts of the hydrophobic peptide backbone of a-Syn, the so called non-amyloid component (NAC), have been also detected in amyloid plaques of Alzheimer’s disease (AD) patients. Although Syns are highly conserved, the hydrophobic NAC region is absent in the protein structure of ß-Syn. The lack of this region might be the reason for the anti-aggregatory properties of ß-Syn towards a-Syn and amyloid aggregation. Additionally, ß-Syn interacts with several intracellular signaling and regulatory pathways such as the apoptotic cascade and the PI3K/AKT signaling. Thus, the aim of this study was to elucidate if ß-Syn overexpression can influence amyloid pathology in vitro and in vivo. At AD pathology onset, lentiviral particles were directly injected into the hippocampus of mice overexpressing human APP with Swedish and London mutations (hAPPSL). Lentiviral particles either encoded for human ß-Syn (hß-Syn) or for an empty lentiviral vector (negative control). After 1, 3 and 6 months, cognitive behavioral analyses were performed. Amyloid pathology was then analyzed biochemically and histologically. In vitro, two different cell culture models were investigated. Human neuroblastoma cells stably overexpressing ß-Syn were studied in comparison to human neuroglioma cells expressing human amyloid precursor protein (APP) infected with ß-Syn expressing lentiviral particles. Local expression of hß-Syn in APPSL animals influenced amyloid pathology in a diverging manner. One and six months after stereotactical injections, hß-Syn counteracted amyloid pathology by reducing APP expression, aggregation and astrocytosis. In contrast, 3 months after the treatment aggregation and astrocytosis were deteriorated after hß-Syn treatment. In addition, exogenous hß-Syn enhanced the phosphorylation of glycogen synthase 3ß (GSK3ß), a known TAU kinase, in vivo and in vitro. Consequently, TAU phosphorylation was altered after ß-Syn overexpression in human neuroblastoma cells. Additionally to the initially reported beneficial effects, adverse consequences of ß-Syn on amyloid expression and aggregation were observed. ß-Syn not only ameliorated amyloid pathology, but also caused neurodegeneration. Besides amyloid pathology, ß-Syn rather seems to influence TAU phosphorylation via the regulation of GSK3ß. Nevertheless, to clarify the exact mechanisms of ß-Syn in AD pathology further examinations considering concentration and exposure time are required.