Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

Sep 18, 2010The Journal of biological chemistry

Higher levels of human apolipoprotein A-I protect memory and reduce brain inflammation and blood vessel amyloid in a mouse model of Alzheimer’s disease

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

APP/PS1/AI triple transgenic mice exhibit a 2-fold increase in plasma HDL cholesterol levels.

Increasing levels of human apolipoprotein A-I may prevent age-related learning and memory deficits in APP/PS1 mice.
No significant differences were observed in the total level and deposition of amyloid-β in the brains of APP/PS1 and APP/PS1/AI mice.
Cerebral amyloid angiopathy was reduced in APP/PS1/AI mice compared to APP/PS1 mice.
Glial activation was decreased in the brains of APP/PS1/AI mice, indicating reduced neuroinflammation.
Aβ-induced production of proinflammatory chemokines and cytokines was decreased in hippocampal slice cultures expressing human apoA-I.

AI simplified

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.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief