title: Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice.
abstract: A hallmark of Alzheimer disease (AD) is the deposition of amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ(40) aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of Aβ(42) and decreases Aβ(42) toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1ΔE9 to apoA-I(KO) mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1ΔE9 mice. Further characterization of APP/PS1ΔE9/apoA-I(KO) mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Aβ oligomer levels, Aβ plaque load, or levels of insoluble Aβ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Aβ isolated from cerebral blood vessels. Our data show that in APP/PS1ΔE9/apoA-I(KO) mice, insoluble Aβ(40) is increased more than 10-fold, and Aβ(42) is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1ΔE9/apoA-I(KO) mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Aβ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1ΔE9 mice in parallel to significantly increased cerebral amyloid angiopathy.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA. iliyal@pitt.edu
authors.forename: Iliya
authors.initials: I
authors.lastname: Lefterov
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Fitz
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Cronican
authors.forename: Allison
authors.initials: A
authors.lastname: Fogg
authors.forename: Preslav
authors.initials: P
authors.lastname: Lefterov
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
authors.forename: Radosveta
authors.initials: R
authors.lastname: Koldamova
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology*; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D018782:Maze Learning; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D053764:Presenilin-1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D016564:Amyloid beta-Protein Precursor; D016632:Apolipoprotein A-I; D053764:Presenilin-1; D012333:RNA, Messenger; D002784:Cholesterol