title: LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Sophie
authors.initials: S
authors.lastname: Stukas
authors.affiliation: National Institutes of Health, Bethesda, MD 20892-1508.
authors.forename: Lita
authors.initials: L
authors.lastname: Freeman
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.affiliation: National Institutes of Health, Bethesda, MD 20892-1508.
authors.forename: Alice
authors.initials: A
authors.lastname: Ossoli
authors.affiliation: National Institutes of Health, Bethesda, MD 20892-1508.
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.affiliation: National Institutes of Health, Bethesda, MD 20892-1508.
authors.forename: Stephen
authors.initials: S
authors.lastname: Demosky
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Jeniffer
authors.initials: J
authors.lastname: Chan
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Veronica
authors.initials: V
authors.lastname: Hirsch-Reinshagen
authors.affiliation: National Institutes of Health, Bethesda, MD 20892-1508.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016632:Apolipoprotein A-I; D007862:Phosphatidylcholine-Sterol O-Acyltransferase
keywords: Alzheimer’s disease; apolipoproteins; high density lipoprotein metabolism; lecithin:cholesterol acyltransferase