title: Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease.
abstract: To date there is no effective therapy for Alzheimer disease (AD). High levels of circulating high density lipoprotein (HDL) and its main protein, apolipoprotein A-I (apoA-I), reduce the risk of cardiovascular disease. Clinical studies show that plasma HDL cholesterol and apoA-I levels are low in patients with AD. To investigate if increasing plasma apoA-I/HDL levels ameliorates AD-like memory deficits and amyloid-β (Aβ) deposition, we generated a line of triple transgenic (Tg) mice overexpressing mutant forms of amyloid-β precursor protein (APP) and presenilin 1 (PS1) as well as human apoA-I (AI). Here we show that APP/PS1/AI triple Tg mice have a 2-fold increase of plasma HDL cholesterol levels. When tested in the Morris water maze for spatial orientation abilities, whereas APP/PS1 mice develop age-related learning and memory deficits, APP/PS1/AI mice continue to perform normally during aging. Interestingly, no significant differences were found in the total level and deposition of Aβ in the brains of APP/PS1 and APP/PS1/AI mice, but cerebral amyloid angiopathy was reduced in APP/PS1/AI mice. Also, consistent with the anti-inflammatory properties of apoA-I/HDL, glial activation was reduced in the brain of APP/PS1/AI mice. In addition, Aβ-induced production of proinflammatory chemokines/cytokines was decreased in mouse organotypic hippocampal slice cultures expressing human apoA-I. Therefore, we conclude that overexpression of human apoA-I in the circulation prevents learning and memory deficits in APP/PS1 mice, partly by attenuating neuroinflammation and cerebral amyloid angiopathy. These findings suggest that elevating plasma apoA-I/HDL levels may be an effective approach to preserve cognitive function in patients with AD.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Lewis
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Cao
authors.forename: Hailin
authors.initials: H
authors.lastname: Lu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mans
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.forename: Lisa
authors.initials: L
authors.lastname: Jungbauer
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
authors.forename: Ling
authors.initials: L
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D058847:Inflammasomes; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008074:Lipoproteins / Q000097:blood; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia; D009154:Mutation / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D053764:Presenilin-1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: C505693:APOA1 protein, human; C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016632:Apolipoprotein A-I; D058847:Inflammasomes; D008074:Lipoproteins; D053764:Presenilin-1; D012333:RNA, Messenger; D002784:Cholesterol