Proposed mechanism for lipoprotein remodelling in the brain

Abstract

Lipoprotein remodelling in the periphery has been extensively studied. For example, the processing of nascent apoAI particles to cholesterol-loaded HDL lipoproteins during reverse cholesterol transport involves a series of enzymes, transporters in peripheral tissue, as well as other apolipoproteins and lipoproteins. These extensive modifications and interconversions are well defined. Here, we present the hypothesis that a similar process occurs within the blood brain barrier (BBB) via glia-secreted lipid-poor apoE particles undergoing remodelling to become mature central nervous system (CNS) lipoproteins. We further pose several pressing issues and future directions for the study of lipoproteins in the brain.

Figure 1. ApoAI-mediated reverse cholesterol transport

Lipid-poor particles are secreted by the liver, take up lipid in the periphery and are cleared by the liver. See description in text and Tables 1 and 2 (Adapted from [2], see also [1, 3]).

Figure 2. Lipid distribution in human CSF and rat glial lipoproteins

50ml of CSF or serum-free glial conditioned media were concentrated to 1ml and fractionated by size exclusion chromatography with tandem Superose-6 columns, and the resulting fractions analysed for lipid. Adapted from [17].

Figure 3. Negative stained electron micrographs of lipoproteins isolated by gel chromatography

A concentrated aliquot (0.5mg/ml of protein) from CSF (inset) and astrocyte media was placed on a carbon coated EM grid and negatively stained with 1% uranyl acetate. Magnification 500,000 X. Adapted from [17].

Figure 4. Hypothesis for lipoprotein remodelling in the parenchyma of the brain

1) Nascent apoE-containing particles are secreted by glial cells. 2) ABCA1 in glia and neurons promotes FC efflux to the nascent particles, followed by additional FC efflux by ABCG1. The result is an intermediate particle(s). 3) Intermediate particle(s) become mature CNS lipoproteins by a poorly understood process that includes acquiring a CE core and additional PL.