title: Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice.
abstract: Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Robert
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Stukas
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Button
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Wai Hang
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jianjia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Iva
authors.initials: I
authors.lastname: Kulic
authors.affiliation: Cardiovascular Therapeutics, CSL Limited, Parkville, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: wcheryl@mail.ubc.ca.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000686:Amyloidosis / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: ABCA1; Alzheimer's Disease; Amyloid beta; ApoA-I; Reconstituted HDL