| First Author | Zandl-Lang M | Year | 2018 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 1 | Pages | 40-60 |
| PubMed ID | 28941799 | Mgi Jnum | J:254181 |
| Mgi Id | MGI:6104418 | Doi | 10.1016/j.bbalip.2017.09.008 |
| Citation | Zandl-Lang M, et al. (2018) Regulatory effects of simvastatin and apoJ on APP processing and amyloid-beta clearance in blood-brain barrier endothelial cells. Biochim Biophys Acta 1863(1):40-60 |
| abstractText | Amyloid-beta peptides (Abeta) 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 Abeta metabolism is evident, the interconnecting mechanisms operating in brain capillary endothelial cells (BCEC) are poorly understood. ApoJ (clusterin) is present in HDL that regulates cholesterol metabolism which is disturbed in AD. ApoJ levels are increased in AD brains and in plasma of cerebral amyloid angiopathy (CAA) patients. ApoJ may bind, prevent fibrillization, and enhance clearance of Abeta. We here define a connection of apoJ and cellular cholesterol homeostasis in amyloid precursor protein (APP) processing/Abeta metabolism at the BBB. Silencing of apoJ in primary porcine (p)BCEC decreased intracellular APP and Abeta oligomer levels while the addition of purified apoJ to pBCEC increased intracellular APP and enhanced Abeta clearance across the pBCEC monolayer. Treatment of pBCEC with Abeta(1-40) increased expression of apoJ and receptors involved in amyloid transport including lipoprotein receptor-related protein 1 [LRP1]. In accordance, cerebromicrovascular endothelial cells isolated from 3xTg AD mice showed elevated expression levels of apoJ and LRP1 as compared to Non-Tg animals. Treatment of pBCEC with HMGCoA-reductase inhibitor simvastatin markedly increased intracellular and secreted apoJ levels, in parallel increased secreted Abeta oligomers and reduced Abeta uptake and cell-associated Abeta oligomers. Simvastatin effects on apoJ, APP processing, and LRP1 expression in BCEC were confirmed in the mouse model. We suggest a close and complex interaction of apoJ, cholesterol homeostasis, and APP/Abeta processing and clearance at the BBB. |
