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Selected Publication:
Zandl-Lang, M.
Interactions of simvastatin and apoJ with APP processing and amyloid-ß clearance in blood-brain barrier endothelial cells
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 134
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- Authors Med Uni Graz:
- Zandl-Lang Martina
- Advisor:
- Panzenboeck Ute
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- Abstract:
- Background: Amyloid-ß peptides (Aß) may accumulate in cerebral capillaries indicating a central role of the blood-brain barrier (BBB) in the pathogenesis of Alzheimer’s disease (AD). Although a relationship between apolipoprotein-, cholesterol- and Aß metabolism is evident, the interconnecting mechanisms operating in brain capillary endothelial cells (BCEC) are poorly understood. Apolipoprotein (apo)J, also known as clusterin, is present in lipoprotein particles and regulates cholesterol and lipid metabolism of brain which is disturbed in AD. ApoJ expression is increased in AD brains and apoJ binds, prevents fibrillization, and enhances endocytosis of Aß. Aims: Our aim was to define the involvement of apoJ and cellular cholesterol homeostasis in amyloid precursor protein (APP) processing/Aß metabolism at the BBB. Primary porcine (p)BCEC were incubated in the presence and absence of plasma-derived apoJ and modulators of cholesterol metabolism prior to analyses of APP/Aß and apoJ mRNA and protein expression levels. In vivo studies with aged 3xTg AD and Non-Tg mice (64±4 weeks) and apoJ ko mice treated for 21 days with the HMGCoA-reductase inhibitor simvastatin [40 mg/kg] by oral gavage were aiming to elucidate the role of cellular cholesterol homeostasis and apoJ in APP metabolism at the BBB in greater detail. Results: RNA interference-mediated silencing of apoJ in pBCEC decreased intracellular APP and Aß oligomer levels by 59% and 56%, respectively, while the addition of 2 or 20 µg/ml of purified apoJ to pBCEC increased intracellular APP (by 3.3 and 2.4-fold, respectively) and enhanced Aß clearance across the in vitro model of the BBB. Cerebromicrovascular endothelial cells isolated from 3xTg AD mice revealed 3.4-fold higher expression levels of apoJ as compared to Non-Tg animals. Treatment with simvastatin markedly increased intracellular and secreted apoJ levels in pBCEC, and, in parallel, increased secreted Aß oligomers, and reduced Aß uptake and cell-associated Aß oligomers. In accordance, simvastatin increased protein levels of apoJ in primary murine (m)BCEC of Non-Tg mice by 73%. In mBCEC of apoJ ko mice, on the other hand, we detected enhanced levels of C-terminal fragments (CTFs) - cleavage products of APP-, which were further increased in response to simvastatin treatment. Conclusion: Our results, so far, suggest a close and complex interaction of cellular cholesterol homeostasis, apoJ, and APP/Aß processing and clearance at the BBB.