J. Neurochem. (2011) 119, 1016–1028. Abstract Currently, little is known about the role of intracellular triacylglycerol (TAG) lipases in the brain. Adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate‐limiting step of lipolysis. In this study, we investigated the effects of ATGL deficiency on brain lipid metabolism in vivo using an established knock‐out mouse model (ATGL‐ko). A moderate decrease in TAG hydrolase activity detected in ATGL‐ko versus wild‐type brain tissue was accompanied by a 14‐fold increase in TAG levels and an altered composition of TAG‐associated fatty acids in ATGL‐ko brains. Oil Red O staining revealed a severe accumulation of neutral lipids associated to cerebrovascular cells and in distinct brain regions namely the ependymal cell layer and the choroid plexus along the ventricular system. In situ hybridization histochemistry identified ATGL mRNA expression in ependymal cells, the choroid plexus, pyramidal cells of the hippocampus, and the dentate gyrus. Our findings imply that ATGL is involved in brain fatty acid metabolism, particularly in regions mediating transport and exchange processes: the brain–CSF interface, the blood–CSF barrier, and the blood–brain barrier.

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Click here to view linked References HIGHLIGHTS 1) Asx exerts beneficial effects similar to Bex in brain capillary endothelial cells 2) non-amyloidogenic APP processing is enhanced via BACE1 and ADAM10 modulation 3) ABCA1 is upregulated and cellular cholesterol efflux is stimulated involving nuclear receptor-dependent mechanisms 4) LRP-1 is up regulated along with augmented Aβ uptake/transcytosis 5) Silencing of LRP-1 or inhibition of ABCA1 reverses effects of Asx and Bex on APP processing/Aß species 6) Asx and Bex considerably reduce cerebral and cerebrovascular Aβ load in vivo in 3xTg

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 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.

Background: Liver X receptor activation promotes formation of HDL-like particles at the blood-brain barrier (BBB). Results: Cerebrovascular endothelial cells express phospholipid transfer protein (PLTP) that transfers phospholipids, remodels HDL, and supports cellular cholesterol efflux. Conclusion: PLTP is involved in HDL genesis and remodeling at the BBB. Significance: We demonstrate a direct role of PLTP in HDL metabolism at the blood-brain interface.