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

Terry L. Lewis, Dongfeng Cao, Hailin Lu, Robert A. Mans, Yan Ru Su, Lisa Jungbauer, MacRae F. Linton, Sergio Fazio, Mary Jo LaDu, Ling Li

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)36958-36968
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number47
DOIs
StatePublished - Nov 19 2010
Externally publishedYes

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Cerebral Amyloid Angiopathy
Apolipoprotein A-I
Amyloid
Amyloid beta-Protein Precursor
Cognition
Presenilin-1
Alzheimer Disease
HDL Lipoproteins
Memory Disorders
Plasmas
Data storage equipment
HDL Cholesterol
Transgenic Mice
Brain
human APOA1 protein
Learning
Chemokines
Neuroglia
Anti-Inflammatory Agents
Cardiovascular Diseases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of alzheimer disease. / Lewis, Terry L.; Cao, Dongfeng; Lu, Hailin; Mans, Robert A.; Su, Yan Ru; Jungbauer, Lisa; Linton, MacRae F.; Fazio, Sergio; LaDu, Mary Jo; Li, Ling.

In: Journal of Biological Chemistry, Vol. 285, No. 47, 19.11.2010, p. 36958-36968.

Research output: Contribution to journalArticle

Lewis, Terry L. ; Cao, Dongfeng ; Lu, Hailin ; Mans, Robert A. ; Su, Yan Ru ; Jungbauer, Lisa ; Linton, MacRae F. ; Fazio, Sergio ; LaDu, Mary Jo ; Li, Ling. / Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of alzheimer disease. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 47. pp. 36958-36968.
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AU - Lu, Hailin

AU - Mans, Robert A.

AU - Su, Yan Ru

AU - Jungbauer, Lisa

AU - Linton, MacRae F.

AU - Fazio, Sergio

AU - LaDu, Mary Jo

AU - Li, Ling

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