Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease.

Lewis TL, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L
J Biol Chem. 2010 285 (47): 36958-68

PMID: 20847045 · PMCID: PMC2978624 · DOI:10.1074/jbc.M110.127829

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.

MeSH Terms (32)

Amyloid beta-Peptides Amyloid beta-Protein Precursor Animals Apolipoprotein A-I Behavior, Animal Blotting, Western Brain Cells, Cultured Cerebral Amyloid Angiopathy Cholesterol Cognition Disorders Disease Models, Animal Embryo, Mammalian Enzyme-Linked Immunosorbent Assay Humans Immunoenzyme Techniques Inflammasomes Inflammation Lipoproteins Maze Learning Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microglia Mutation Myocytes, Smooth Muscle Presenilin-1 Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Sequence Deletion Signal Transduction

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