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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-? (A?) deposition, we generated a line of triple transgenic (Tg) mice overexpressing mutant forms of amyloid-? 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 A? 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, A?-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.

SUBMITTER: Lewis TL

PROVIDER: S-EPMC2978624 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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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 TL Cao Dongfeng D Lu Hailin H Mans Robert A RA Su Yan Ru YR Jungbauer Lisa L Linton MacRae F MF Fazio Sergio S LaDu Mary Jo MJ Li Ling L

The Journal of biological chemistry 20100916 47

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 overexpressin ...[more]

PMID: 20847045

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Project description:BackgroundBoth cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA) are related to cognitive impairment and dementia. This study aimed to clarify CAA- and HA-related small vessel disease (SVD) imaging marker associations with cognitive dysfunction and Alzheimer disease (AD) subtypes.MethodsA sample of 137 subjects with clinically diagnosed late-onset AD identified from the dementia registry of a single center from January 2017 to October 2021 were enrolled. Semi-quantitative imaging changes (visual rating scale grading) suggestive of SVD were analyzed singularly and compositely, and their correlations with cognitive domains and AD subtypes were examined.ResultsPatients with typical and limbic-predominant AD subtypes had worse cognitive performance and higher dementia severity than minimal-atrophy subtype patients. Deep white matter hyperintensity (WMH) presence correlated inversely with short-term memory (STM) performance. The three composite SVD scores correlated with different cognitive domains and had distinct associations with AD subtypes. After adjusting for relevant demographic factors, multivariate logistic regression (using minimal-atrophy subtype as the reference condition) revealed the following: associations of the typical subtype with periventricular WMH [odds ratio (OR) 2.62; 95% confidence interval (CI), 1.23-5.57, p = 0.012], global SVD score (OR 1.67; 95%CI, 1.11-2.52, p = 0.009), and HA-SVD score (OR 1.93; 95%CI, 1.10-3.52, p = 0.034); associations of limbic-predominant subtype with HA-SVD score (OR 2.57; 95%CI, 1.23-5.37, p = 0.012) and most global and domain-specific cognitive scores; and an association of hippocampal-sparing subtype with HA-SVD score (OR 3.30; 95%CI, 1.58-6.85, p = 0.001).ConclusionComposite SVD imaging markers reflect overall CAA and/or HA severity and may have differential associations with cognitive domains and AD subtypes. Our finding supports the possibility that the clinical AD subtypes may reflect differing burdens of underlying CAA and HA microangiopathologies.

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Dataset Information

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

Publications

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

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