Localization of lipoprotein lipase to discrete areas of the guinea pig brain

The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hippocampal regions in both human control and AD brains. Interestingly, apoC-I colocalized with b-amyloid (Ab) in plaques in AD brains, and in vitro experiments revealed that aggregation of Ab was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble Ab oligomer-induced neuronal death. To establish a potential role for apoC-I in cognitive functions, we used human (h) APOC1 1/0 transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1 1/0 mice displayed impaired hippocampal-dependent learning and memory functions compared with their wild-type littermates, as judged from their performance in the object recognition task (P 5 0.012) and in the Morris water maze task (P 5 0.010). ApoC-I may affect learning as a result of its inhibitory properties toward apoE-dependent lipid metabolism. However, no differences in brain mRNA or protein levels of endogenous apoE were detected between transgenic and wild-type mice. In conclusion, human apoC-I expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoC-I during the development of

Section: Discussionmentioning

confidence: 99%

Human apolipoprotein C-I expression in mice impairs learning and memory functions

Abildayeva

Berbée

Blokland

et al. 2008

“…First, the capillaries of the brain-an organ that uses glucose for fuel-express almost no Gpihbp1 , while certain regions of the brain, notably the hippocampus, express large amounts of Lpl (69)(70)(71)(72)(73). The explanation for this discrepancy is unknown, but one potential explanation is that LPL in the brain is not transported into capillaries and functions in the extravascular compartment.…”

Section: G Fong S G Young Unpublished Observations)mentioning

confidence: 99%

“…LPL is expressed highly in certain regions of the brain, as judged by in situ hybridization (69)(70)(71)(72)(73), but there is little GPIHBP1 in the brain. What underlies this discrepancy?…”

Section: Fig 14mentioning

confidence: 99%

GPIHBP1, an endothelial cell transporter for lipoprotein lipase

Young

Davies

Voss

et al. 2011

101

Interest in lipolysis and the metabolism of triglyceride-rich lipoproteins was recently reignited by the discovery of severe hypertriglyceridemia (chylomicronemia) in glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 ( GPIHBP1)-defi cient mice. GPI-HBP1 is expressed exclusively in capillary endothelial cells and binds lipoprotein lipase (LPL) avidly. These fi ndings prompted speculation that GPIHBP1 serves as a binding site for LPL in the capillary lumen, creating "a platform for lipolysis." More recent studies have identifi ed a second and more intriguing role for GPIHBP1-picking up LPL in the subendothelial spaces and transporting it across endothelial cells to the capillary lumen. Here, we review the studies that revealed that GPIHBP1 is the LPL transporter and discuss which amino acid sequences are required for GPI-HBP1-LPL interactions. We also discuss the human genetics of LPL transport, focusing on cases of chylomicronemia caused by GPIHBP1 mutations that abolish GPIHBP1's ability to bind LPL, and LPL mutations that prevent LPL binding to GPIHBP1. The outline for the lipolytic processing of lipoproteins has been established for decades ( 1, 2 ). Triglyceride-rich Abbreviations: ANGPTL, angiopoietin-like protein; BODIPY, borondipyrromethane; CHO, Chinese hamster ovary; cLPL, chicken lipoprotein lipase; DiI, 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate; EL, endothelial lipase; GPI, glycosylphosphatidylinositol; GPIHBP1, glycosylphosphatidylinositol -anchored high density lipoprotein-binding protein 1; HSPG, heparan sulfate proteoglycan; Ly6, Lymphocyte Antigen 6; PIPLC, phosphatidylinositol-specifi c phospholipase C; SR-BI, scavenger receptor class B, type 1. This work was supported by a Scientist Development Award from the American Heart Association, National Offi ce (to A.P.B.), R01 HL094732 (to A.P.B.), P01 HL090553 (to S.G.Y.), and R01 HL087228 (to S.G.Y.). The authors have declared that no confl ict of interest exists. Manuscript received 28 June 2011 and in revised form

“…The expression of LPL mRNA is most impressive in the CA1, CA2, and CA4 layers of the hippocampus (68). This area is well recognized to be the learning center of the brain, where hippocampal neurons contribute to memory by rapidly assimilating information about the perceptual and behavioral structure of experience.…”

Section: Lpl In Neurological Tissuesmentioning

confidence: 99%

Lipoprotein lipase

Merkel

Eckel

Goldberg

2002

464

113

Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1 ) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2 ) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3 ) LPL gene regulation: the LPL promoter and its regulatory elements are described. -Merkel, M., R. H. Eckel, and I. J. Goldberg. Lipoprotein lipase: genetics, lipid uptake, and regulation.