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Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Jan;1863(1):40-60. doi: 10.1016/j.bbalip.2017.09.008. Epub 2017 Sep 20.

Regulatory effects of simvastatin and apoJ on APP processing and amyloid-β clearance in blood-brain barrier endothelial cells.

Author information

1
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
2
Molecular Neurodegeneration, Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
3
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute Huddinge, Huddinge, Sweden.
4
Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Rudjer Boskovic Institute, Zagreb, Croatia.
5
School of Biological Sciences, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
6
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. Electronic address: ute.panzenboeck@medunigraz.at.

Abstract

Amyloid-β peptides (Aβ) 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 Aβ 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 Aβ. We here define a connection of apoJ and cellular cholesterol homeostasis in amyloid precursor protein (APP) processing/Aβ metabolism at the BBB. Silencing of apoJ in primary porcine (p)BCEC decreased intracellular APP and Aβ oligomer levels while the addition of purified apoJ to pBCEC increased intracellular APP and enhanced Aβ clearance across the pBCEC monolayer. Treatment of pBCEC with Aβ(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 3×Tg 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 Aβ oligomers and reduced Aβ uptake and cell-associated Aβ 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/Aβ processing and clearance at the BBB.

KEYWORDS:

Alzheimer disease; Amyloid-beta (Aβ); Blood-brain barrier; Cholesterol metabolism; Clusterin/apoJ; Endothelium

PMID:
28941799
DOI:
10.1016/j.bbalip.2017.09.008
[Indexed for MEDLINE]

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