Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice

Oct 11, 2015Biochimica et biophysica acta

High-density lipoproteins quickly lower soluble brain amyloid-beta levels in mice with Alzheimer's symptoms

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Abstract

A single intravenous dose of 60 mg/kg of reconstituted HDL reduced soluble brain amyloid beta levels within 24 hours in symptomatic APP/PS1 mice.

Reconstituted HDL (rHDL) is composed of human apoA-I and soy phosphatidylcholine.
In the acute study, both Aβ40 and Aβ42 levels in the brain significantly decreased following rHDL administration.
No significant changes in soluble or deposited Aβ levels were observed in the chronic study conducted 7 days after the final rHDL dose.
The lack of persistent effects in the chronic study suggests that the beneficial action of rHDL may be short-lived.
There were no observed changes in amyloid burden, cerebrospinal fluid Aβ levels, neuroinflammation, or endothelial activation in the chronic study.

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Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

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Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice

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