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• W2049981208 abstract "A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating β-amyloid (Aβ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aβ clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aβ or amyloid in APP/PS1 LCAT−/− mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aβ clearance. A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating β-amyloid (Aβ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aβ clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aβ or amyloid in APP/PS1 LCAT−/− mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aβ clearance. Lipoprotein metabolism in the CNS is intimately involved in the progression and pathogenesis of Alzheimer's disease (AD) (1Verghese P.B. Castellano J.M. Holtzman D.M. Apolipoprotein E in Alzheimer's disease and other neurological disorders.Lancet Neurol. 2011; 10: 241-252Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar). Since the 1993 discovery that inheritance of the apoE4 allele increases risk and decreases the age of onset of late-onset AD (2Corder E.H. Saunders A.M. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Small G.W. Roses A.D. Haines J.L. Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (7251) Google Scholar), the putative roles of apoE in AD pathogenesis have been a topic of intensive focus. apoE is the primary apolipoprotein secreted by astrocytes and microglia in the CNS, and lipidation of nascent apoE-containing discoidal particles eventually leads to the formation of mature CNS HDL-like particles in cerebrospinal fluid (CSF) (1Verghese P.B. Castellano J.M. Holtzman D.M. Apolipoprotein E in Alzheimer's disease and other neurological disorders.Lancet Neurol. 2011; 10: 241-252Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar, 3Stukas S. Robert J. Wellington C.L. High density lipoproteins and cerebrovasular integrity in Alzheimer's disease.Cell Metab. 2014; 19: 574-591Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). It is well-established that amyloid burden in humans follows an isoform-dependent pattern of apoE4>apoE3>apoE2 (4Strittmatter W.J. Saunders A.M. Schmechel D. Pericak-Vance M. Enghild J. Salvesen G.S. Roses A.D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.Proc. Natl. Acad. Sci. USA. 1993; 90: 1977-1981Crossref PubMed Scopus (3693) Google Scholar, 5Schmechel D.E. Saunders A.M. Strittmatter W.J. Crain B.J. Hulette C.M. Joo S.H. Pericak-Vance M.A. Goldgaber D. Roses A.D. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.Proc. Natl. Acad. Sci. USA. 1993; 90: 9649-9653Crossref PubMed Scopus (1347) Google Scholar, 6Polvikoski T. Sulkava R. Haltia M. Kainulainen K. Vuorio A. Verkkoniemi A. Niinisto L. Halonen P. Kontula K. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.N. Engl. J. Med. 1995; 333: 1242-1247Crossref PubMed Scopus (444) Google Scholar). In contrast to human apoE, murine apoE exists in only one isoform with limited homology to human apoE. Amyloid burden is robust in AD mice expressing murine apoE and nearly abrogated in apoE-deficient mice (7Holtzman D.M. Fagan A.M. Mackey B. Tenkova T. Sartorius L. Paul S.M. Bales K. Ashe K.H. Irizarry M.C. Hyman B.T. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model.Ann. Neurol. 2000; 47: 739-747Crossref PubMed Scopus (266) Google Scholar, 8Irizarry M.C. Rebeck G.W. Cheung B. Bales K. Paul S.M. Holzman D. Hyman B.T. Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background.Ann. N. Y. Acad. Sci. 2000; 920: 171-178Crossref PubMed Scopus (52) Google Scholar, 9Bales K.R. Verina T. Cummins D.J. Du Y. Dodel R.C. Saura J. Fishman C.E. DeLong C.A. Piccardo P. Petegnief V. et al.Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 1999; 96: 15233-15238Crossref PubMed Scopus (415) Google Scholar, 10Bales K.R. Verina T. Dodel R.C. Du Y. Altstiel L. Bender M. Hyslop P. Johnstone E.M. Little S.P. Cummins D.J. et al.Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.Nat. Genet. 1997; 17: 263-264Crossref PubMed Scopus (705) Google Scholar, 11Fryer J.D. Taylor J.W. DeMattos R.B. Bales K.R. Paul S.M. Parsadanian M. Holtzman D.M. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.J. Neurosci. 2003; 23: 7889-7896Crossref PubMed Google Scholar). Reconstitution of human apoE isoforms into AD mice greatly delays amyloid deposition relative to murine apoE, but retains the human isoform-specific influence on amyloid accumulation (12Holtzman D.M. Bales K.R. Tenkova T. Fagan A.M. Parsadanian M. Sartorius L.J. Mackey B. Olney J. McKeel D. Wozniak D. et al.Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2000; 97: 2892-2897Crossref PubMed Scopus (729) Google Scholar, 13Fagan A.M. Watson M. Parsadanian M. Bales K.R. Paul S.M. Holtzman D.M. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol. Dis. 2002; 9: 305-318Crossref PubMed Scopus (219) Google Scholar, 14Fryer J.D. Simmons K. Parsadanian M. Bales K.R. Paul S.M. Sullivan P.M. Holtzman D.M. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.J. Neurosci. 2005; 25: 2803-2810Crossref PubMed Scopus (228) Google Scholar, 15Bales K.R. Liu F. Wu S. Lin S. Koger D. DeLong C. Hansen J.C. Sullivan P.M. Paul S.M. Human APOE isoform-dependent effects on brain β-amyloid levels in PDAPP transgenic mice.J. Neurosci. 2009; 29: 6771-6779Crossref PubMed Scopus (202) Google Scholar, 16Castellano J.M. Kim J. Stewart F.R. Jiang H. DeMattos R.B. Patterson B.W. Fagan A.M. Morris J.C. Mawuenyega K.G. Cruchaga C. et al.Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.Sci. Transl. Med. 2011; 3: 89ra57Crossref PubMed Scopus (783) Google Scholar, 17Kim J. Jiang H. Park S. Eltorai A.E. Stewart F.R. Yoon H. Basak J.M. Finn M.B. Holtzman D.M. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis.J. Neurosci. 2011; 31: 18007-18012Crossref PubMed Scopus (139) Google Scholar). Taken together, the relative amyloid burden across murine and human apoE is: murine apoE>>apoE4>apoE3>apoE2>>apoE−/−. These observations clearly show that apoE affects amyloid burden in vivo. In vivo, neither apoE isoform nor gene dose significantly affects the rate of β-amyloid (Aβ) production from amyloid precursor protein (16Castellano J.M. Kim J. Stewart F.R. Jiang H. DeMattos R.B. Patterson B.W. Fagan A.M. Morris J.C. Mawuenyega K.G. Cruchaga C. et al.Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.Sci. Transl. Med. 2011; 3: 89ra57Crossref PubMed Scopus (783) Google Scholar, 17Kim J. Jiang H. Park S. Eltorai A.E. Stewart F.R. Yoon H. Basak J.M. Finn M.B. Holtzman D.M. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis.J. Neurosci. 2011; 31: 18007-18012Crossref PubMed Scopus (139) Google Scholar), leading to the consensus that apoE is largely involved in modulating the clearance of Aβ peptides from the brain. apoE participates in each of the three known pathways of Aβ clearance, including proteolytic degradation, egress across the blood-brain barrier, and interstitial fluid drainage, although many details remain poorly understood (18Sagare A.P. Bell R.D. Zlokovic B.V. Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2012; 2: a011452Crossref PubMed Scopus (184) Google Scholar, 19Saido T. Leissring M.A. Proteolytic degradation of amyloid β-protein.Cold Spring Harb. Perspect. Med. 2012; 2: a006379Crossref PubMed Scopus (243) Google Scholar). It is important to note, however, that apoE isoforms, levels, and lipidation status are all important variables. With respect to apoE levels, most studies suggest that apoE promotes retention of Aβ in the brain, as brain-to-blood transport of radiolabeled Aβ injected into the brain is slowed when premixed with human apoE compared with free Aβ (20Deane R. Sagare A. Hamm K. Parisi M. Lane S. Finn M.B. Holtzman D.M. Zlokovic B.V. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain.J. Clin. Invest. 2008; 118: 4002-4013Crossref PubMed Scopus (562) Google Scholar, 21Bell R.D. Sagare A.P. Friedman A.E. Bedi G.S. Holtzman D.M. Deane R. Zlokovic B.V. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.J. Cereb. Blood Flow Metab. 2007; 27: 909-918Crossref PubMed Scopus (522) Google Scholar). Also supporting this viewpoint is the observation that amyloid burden is lower in hemizygous APOE3 and APOE4 APP/PS1-21 and hAPP J20 AD mice compared with homozygous controls (17Kim J. Jiang H. Park S. Eltorai A.E. Stewart F.R. Yoon H. Basak J.M. Finn M.B. Holtzman D.M. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis.J. Neurosci. 2011; 31: 18007-18012Crossref PubMed Scopus (139) Google Scholar, 22Bien-Ly N. Gillespie A.K. Walker D. Yoon S.Y. Huang Y. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice.J. Neurosci. 2012; 32: 4803-4811Crossref PubMed Scopus (117) Google Scholar). Intriguingly, as a recent microdialysis study showed that very little apoE is actually associated with soluble Aβ in brain interstitial fluid, apoE may retard Aβ clearance from brain to blood by competing with Aβ for binding to the LDL receptor-related protein 1 (LRP1) (23Verghese P.B. Castellano J.M. Garai K. Wang Y. Jiang H. Shah A. Bu G. Frieden C. Holtzman D.M. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions.Proc. Natl. Acad. Sci. USA. 2013; 110: E1807-E1816Crossref PubMed Scopus (344) Google Scholar). However, another study found that there was significant interaction between apoE and Aβ, and that the levels of soluble apoE-Aβ decreased in an isoform-specific manner apoE4<apoE3<apoE2 (24Tai L.M. Bilousova T. Jungbauer L. Roeske S.K. Youmans K.L. Yu C. Poon W.W. Cornwell L.B. Miller C.A. Vinters H.V. et al.Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples.J. Biol. Chem. 2013; 288: 5914-5926Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). These observations suggest that the putative interactions between apoE and Aβ may vary depending on the experimental conditions and pools of apoE and Aβ that are studied. Additionally, brain-specific overexpression of the LDL receptor (LDLR), the major apoE receptor (25Fryer J.D. Demattos R.B. McCormick L.M. O'Dell M.A. Spinner M.L. Bales K.R. Paul S.M. Sullivan P.M. Parsadanian M. Bu G. et al.The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice.J. Biol. Chem. 2005; 280: 25754-25759Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), leads to significantly decreased brain apoE levels and significantly reduced amyloid and Aβ loads, presumably by accelerating apoE uptake (26Castellano J.M. Deane R. Gottesdiener A.J. Verghese P.B. Stewart F.R. West T. Paoletti A.C. Kasper T.R. DeMattos R.B. Zlokovic B.V. et al.Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis.Proc. Natl. Acad. Sci. USA. 2012; 109: 15502-15507Crossref PubMed Scopus (131) Google Scholar, 27Johnson L.A. Olsen R.H. Merkens L.S. DeBarber A. Steiner R.D. Sullivan P.M. Maeda N. Raber J. Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner.Neurobiol. Dis. 2014; 64: 150-162Crossref PubMed Scopus (51) Google Scholar). How apoE is involved in Aβ metabolism is not completely understood, as net levels of apoE are only one part of the equation; the degree to which apoE is lipidated also significantly affects function. Lipidation of apoE in the CNS is performed by ABCA1 (28Hirsch-Reinshagen V. Zhou S. Burgess B.L. Bernier L. McIsaac S.A. Chan J.Y. Tansley G.H. Cohn J.S. Hayden M.R. Wellington C.L. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.J. Biol. Chem. 2004; 279: 41197-41207Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 29Wahrle S.E. Jiang H. Parsadanian M. Legleiter J. Han X. Fryer J.D. Kowalewski T. Holtzman D.M. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE.J. Biol. Chem. 2004; 279: 40987-40993Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar), akin to the well-established role of ABCA1-mediated lipidation of apoA-I in the periphery (30.KoldamovaR.FitzN. F.LefterovI.. ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol. Dis. Epub ahead of print. May 17, 2014; doi:10.1016/j.nbd.2014,05,007.Google Scholar). Plasma and CSF apoA-I levels are markedly reduced in mice deficient in ABCA1, whereas CSF and brain tissue apoE are decreased by 60–80% (28Hirsch-Reinshagen V. Zhou S. Burgess B.L. Bernier L. McIsaac S.A. Chan J.Y. Tansley G.H. Cohn J.S. Hayden M.R. Wellington C.L. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.J. Biol. Chem. 2004; 279: 41197-41207Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 29Wahrle S.E. Jiang H. Parsadanian M. Legleiter J. Han X. Fryer J.D. Kowalewski T. Holtzman D.M. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE.J. Biol. Chem. 2004; 279: 40987-40993Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 31Aiello R.J. Brees D. Francone O.L. ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL formation and inflammation.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 972-980Crossref PubMed Scopus (132) Google Scholar). ABCA1−/− mice display increased insoluble Aβ and amyloid deposition when crossed onto the TgSwDI (32Hirsch-Reinshagen V. Maia L.F. Burgess B.L. Blain J.F. Naus K.E. McIsaac S.A. Parkinson P.F. Chan J.Y. Tansley G.H. Hayden M.R. et al.The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.J. Biol. Chem. 2005; 280: 43243-43256Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar), APP23 (33Koldamova R. Staufenbiel M. Lefterov I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice.J. Biol. Chem. 2005; 280: 43224-43235Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar), and PDAPP (34Wahrle S.E. Jiang H. Parsadanian M. Hartman R.E. Bales K.R. Paul S.M. Holtzman D.M. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.J. Biol. Chem. 2005; 280: 43236-43242Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar) mouse models of AD. Conversely, selective overexpression of ABCA1 by 6-fold or more is sufficient to prevent the formation of amyloid plaques without altering the net levels of CNS apoE or apoA-I in PDAPP mice (35Wahrle S.E. Jiang H. Parsadanian M. Kim J. Li A. Knoten A. Jain S. Hirsch-Reinshagen V. Wellington C.L. Bales K.R. et al.Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.J. Clin. Invest. 2008; 118: 671-682PubMed Google Scholar). Similar to apoA-I-containing HDL particles in plasma, apoE-containing HDL-like particles in the CNS exist in two major structural conformations depending on their maturation state (3Stukas S. Robert J. Wellington C.L. High density lipoproteins and cerebrovasular integrity in Alzheimer's disease.Cell Metab. 2014; 19: 574-591Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In vitro, astrocytes, and to a lesser extent, microglia, secrete several nascent discoidal apoE particles ranging from 7.5 to 17 nm in diameter that contain 0–18% of their cholesterol as esters (36Fan J. Stukas S. Wong C. Chan J. May S. DeValle N. Hirsch-Reinshagen V. Wilkinson A. Oda M.N. Wellington C.L. An ABCA1-independent pathway for recycling a poorly lipidated 8.1 nm apolipoprotein E particle from glia.J. Lipid Res. 2011; 52: 1605-1616Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 37DeMattos R.B. Brendza R.P. Heuser J.E. Kierson M. Cirrito J.R. Fryer J. Sullivan P.M. Fagan A.M. Han X. Holtzman D.M. Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice.Neurochem. Int. 2001; 39: 415-425Crossref PubMed Scopus (130) Google Scholar, 38LaDu M.J. Gilligan S.M. Lukens J.R. Cabana V.G. Reardon C.A. Van Eldik L.J. Holtzman D.M. Nascent astrocyte particles differ from lipoproteins in CSF.J. Neurochem. 1998; 70: 2070-2081Crossref PubMed Scopus (242) Google Scholar, 39Fagan A.M. Holtzman D.M. Munson G. Mathur T. Schneider D. Chang L.K. Getz G.S. Reardon C.A. Lukens J. Shah J.A. et al.Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-), and human apoE transgenic mice.J. Biol. Chem. 1999; 274: 30001-30007Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). By contrast, apoE- and apoA-I-containing lipoprotein particles in CSF are 11–20 nm spherical particles containing 70% of their cholesterol in the esterified form, with a similar density to α-HDL found in plasma (38LaDu M.J. Gilligan S.M. Lukens J.R. Cabana V.G. Reardon C.A. Van Eldik L.J. Holtzman D.M. Nascent astrocyte particles differ from lipoproteins in CSF.J. Neurochem. 1998; 70: 2070-2081Crossref PubMed Scopus (242) Google Scholar, 40Pitas R.E. Boyles J.K. Lee S.H. Hui D. Weisgraber K.H. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain.J. Biol. Chem. 1987; 262: 14352-14360Abstract Full Text PDF PubMed Google Scholar, 41Koch S. Donarski N. Goetze K. Kreckel M. Stuerenburg H.J. Buhmann C. Beisiegel U. Characterization of four lipoprotein classes in human cerebrospinal fluid.J. Lipid Res. 2001; 42: 1143-1151Abstract Full Text Full Text PDF PubMed Google Scholar, 42Demeester N. Castro G. Desrumaux C. De Geitere C. Fruchart J.C. Santens P. Mulleners E. Engelborghs S. De Deyn P.P. Vandekerckhove J. et al.Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease.J. Lipid Res. 2000; 41: 963-974Abstract Full Text Full Text PDF PubMed Google Scholar). Plasma HDL maturation is catalyzed by LCAT, which esterifies free cholesterol (FC) to cholesteryl ester (CE) to form the lipid core critical for conversion of discoidal preβ-HDL to mature spherical α-HDL (43Rousset X. Shamburek R. Vaisman B. Amar M. Remaley A.T. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor?.Curr. Atheroscler. Rep. 2011; 13: 249-256Crossref PubMed Scopus (71) Google Scholar). In addition to HDL, LCAT can also esterify FC contained on other lipoprotein particles, thus influencing their metabolism as well. In plasma, HDL maturation maintains the gradient of FC between the cell membrane and HDL surface, thereby driving cholesterol efflux, a key process in reverse cholesterol transport (43Rousset X. Shamburek R. Vaisman B. Amar M. Remaley A.T. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor?.Curr. Atheroscler. Rep. 2011; 13: 249-256Crossref PubMed Scopus (71) Google Scholar). Plasma α-HDL and apoA-I levels are dramatically reduced in LCAT−/− mice (44Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I.J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 45Sakai N. Vaisman B.L. Koch C.A. Hoyt Jr, R.F. Meyn S.M. Talley G.D. Paiz J.A. Brewer Jr, H.B. Santamarina-Fojo S. Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency.J. Biol. Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar), however the macrophage reverse cholesterol transport pathway is largely preserved (46Tanigawa H. Billheimer J.T. Tohyama J. Fuki I.V. Ng D.S. Rothblat G.H. Rader D.J. Lecithin: cholesterol acyltransferase expression has minimal effects on macrophage reverse cholesterol transport in vivo.Circulation. 2009; 120: 160-169Crossref PubMed Scopus (71) Google Scholar). Whether LCAT is pro- or antiatherogenic remains contested, as results from both animal and human studies are conflicting (43Rousset X. Shamburek R. Vaisman B. Amar M. Remaley A.T. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor?.Curr. Atheroscler. Rep. 2011; 13: 249-256Crossref PubMed Scopus (71) Google Scholar). In the CNS, we have previously shown that LCAT is secreted by astrocytes and is capable of esterifying FC contained on glial-derived nascent apoE-containing particles (47Hirsch-Reinshagen V. Donkin J. Stukas S. Chan J. Wilkinson A. Fan J. Parks J.S. Kuivenhoven J.A. Lutjohann D. Pritchard H. et al.LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins.J. Lipid Res. 2009; 50: 885-893Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). apoE is hypothesized to be the major LCAT activator in the CNS, as apoE is sufficient to stimulate esterification of endogenous cholesterol in glial-conditioned media (39Fagan A.M. Holtzman D.M. Munson G. Mathur T. Schneider D. Chang L.K. Getz G.S. Reardon C.A. Lukens J. Shah J.A. et al.Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-), and human apoE transgenic mice.J. Biol. Chem. 1999; 274: 30001-30007Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). apoA-I, which is not synthesized within the CNS but is found in CSF, is also capable of esterifying cholesterol using glial-derived LCAT (47Hirsch-Reinshagen V. Donkin J. Stukas S. Chan J. Wilkinson A. Fan J. Parks J.S. Kuivenhoven J.A. Lutjohann D. Pritchard H. et al.LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins.J. Lipid Res. 2009; 50: 885-893Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). The levels and activity of LCAT in CSF are estimated to be 2.2–2.5% of serum LCAT (42Demeester N. Castro G. Desrumaux C. De Geitere C. Fruchart J.C. Santens P. Mulleners E. Engelborghs S. De Deyn P.P. Vandekerckhove J. et al.Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease.J. Lipid Res. 2000; 41: 963-974Abstract Full Text Full Text PDF PubMed Google Scholar, 48Albers J.J. Marcovina S.M. Christenson R.H. Lecithin cholesterol acyltransferase in human cerebrospinal fluid: reduced level in patients with multiple sclerosis and evidence of direct synthesis in the brain.Int. J. Clin. Lab. Res. 1992; 22: 169-172Crossref PubMed Scopus (17) Google Scholar). In young C57Bl.6 mice, LCAT deficiency leads to a dramatic increase in apoE and a concurrent decrease of apoA-I levels in CSF (47Hirsch-Reinshagen V. Donkin J. Stukas S. Chan J. Wilkinson A. Fan J. Parks J.S. Kuivenhoven J.A. Lutjohann D. Pritchard H. et al.LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins.J. Lipid Res. 2009; 50: 885-893Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), suggesting that LCAT activity may in part regulate CSF apoE and apoA-I levels. LCAT activity in the CSF of AD subjects has been reported to be up to 50% lower than in cognitively normal subjects (42Demeester N. Castro G. Desrumaux C. De Geitere C. Fruchart J.C. Santens P. Mulleners E. Engelborghs S. De Deyn P.P. Vandekerckhove J. et al.Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease.J. Lipid Res. 2000; 41: 963-974Abstract Full Text Full Text PDF PubMed Google Scholar). It is not known whether this association may be related to Aβ metabolism, such that reduced LCAT may impair Aβ clearance. It is also not known whether aging or the presence of Aβ may impair LCAT activity. To address the question of whether Aβ clearance requires LCAT-mediated maturation of apoE-bearing HDL-like particles, we assessed the impact of LCAT deficiency on soluble and aggregated Aβ levels as well as parenchymal and vascular amyloid burden in the APP/PS1 model of AD. We also assessed the impact of aging and Aβ accumulation on LCAT expression and activity. Here we report that protein levels and plasma activity of LCAT are not altered by age and/or Aβ accumulation and that neither Aβ nor amyloid levels are increased in the absence of LCAT. We conclude that LCAT-mediated cholesterol esterification and maturation of apoE-containing lipoproteins in the CNS is not required for apoE's role in Aβ metabolism. APP/PS1 (line 85) mice (Jackson Laboratories), which coexpress two transgenes from the murine prion promoter: a chimeric mouse/human APP cDNA containing the Swedish (K670M/N671L) mutations and the human PS1 gene deleted for exon 9, were crossed with LCAT−/− animals followed by one backcross to generate male APP/PS1 LCAT−/− mice. Male APP/PS1 mice were analyzed at 15–16 months of age, unless otherwise stated. Animals were maintained on a standard chow diet (PMI LabDiet 5010). All procedures involving experimental animals were approved by the Canadian Council of Animal Care and the University of British Columbia Committee on Animal Care. Mice were anesthetized by intraperitoneal administration of a mixture of 20 mg/kg xylazine (Bayer) and 150 mg/kg ketamine (Bimeda-MTC). CSF was isolated from the cisterna magna as described (49DeMattos R.B. Bales K.R. Parsadanian M. O'Dell M.A. Foss E.M. Paul S.M. Holtzman D.M. Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease.J. Neurochem. 2002; 81: 229-236Crossref PubMed Scopus (224) Google Scholar). Blood was collected via cardiac puncture, placed into tubes containing EDTA, and centrifuged at 21,000 rcf for 10 min and stored at −80°C until use. Animals were then perfused for 7 min at 8 ml/min with PBS containing 2,500 U/l heparin. Liver and brain were extracted and the cortex and hippocam" @default.
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• W2049981208 date "2014-08-01" @default.
• W2049981208 modified "2023-09-25" @default.
• W2049981208 title "LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice" @default.
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• W2049981208 doi "https://doi.org/10.1194/jlr.m049940" @default.
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